Substituted phenyl naphthalenes as estrogenic agents

ABSTRACT

This invention provides estrogen receptor modulators of formula I, having the structure  
                 
 
     wherein  
     R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 , are as defined in the specification, or a pharmaceutically acceptable salt thereof.

[0001] This application claims priority from copending provisionalapplication Serial No. 60/341,164 filed Dec. 13, 2001, the entiredisclosure of which is hereby incorporated by reference.

[0002] This application claims priority from copending provisionalapplication Serial No. 60/341,441 filed Dec. 13, 2001, the entiredisclosure of which is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

[0003] This invention relates to substituted phenyl naphthalenes, whichare useful as estrogenic agents.

[0004] The pleiotropic effects of estrogens in mammalian tissues havebeen well documented, and it is now appreciated that estrogens affectmany organ systems [Mendelsohn and Karas, New England Journal ofMedicine 340: 1801-1811 (1999), Epperson, et al., Psychosomatic Medicine61: 676-697 (1999), Crandall, Journal of Womens Health & Gender BasedMedicine 8: 1155-1166 (1999), Monk and Brodaty, Dementia & GeriatricCognitive Disorders 11: 1-10 (2000), Hum and Macrae, Journal of CerebralBlood Flow & Metabolism 20: 631-652 (2000), Calvin, Maturitas 34:195-210 (2000), Finking, et al., Zeitschrift fur Kardiologie 89: 442-453(2000), Brincat, Maturitas 35: 107-117 (2000), Al-Azzawi, PostgraduateMedical Journal 77: 292-304 (2001)]. Estrogens can exert effects ontissues in several ways, and the most well characterized mechanism ofaction is their interaction with estrogen receptors leading toalterations in gene transcription. Estrogen receptors areligand-activated transcription factors and belong to the nuclear hormonereceptor superfamily. Other members of this family include theprogesterone, androgen, glucocorticoid and mineralocorticoid receptors.Upon binding ligand, these receptors dimerize and can activate genetranscription either by directly binding to specific sequences on DNA(known as response elements) or by interacting with other transcriptionfactors (such as AP1), which in turn bind directly to specific DNAsequences [Moggs and Orphamides, EMBO Reports 2: 775-781 (2001), Hall,et al., Journal of Biological Chemistry 276: 36869-36872 (2001),McDonnell, Principles Of Molecular Regulation. p351-361(2000)]. A classof “coregulatory” proteins can also interact with the ligand-boundreceptor and further modulate its transcriptional activity [McKenna, etal., Endocrine Reviews 20: 321-344 (1999)]. It has also been shown thatestrogen receptors can suppress NFκB-mediated transcription in both aligand-dependent and independent manner [Quaedackers, et al.,Endocrinology 142: 1156-1166 (2001), Bhat, et al., Journal of SteroidBiochemistry & Molecular Biology 67: 233-240 (1998), Pelzer, et al.,Biochemical & Biophysical Research Communications 286: 1153-7 (2001)].

[0005] Estrogen receptors can also be activated by phosphorylation. Thisphosphorylation is mediated by growth factors such as EGF and causeschanges in gene transcription in the absence of ligand [Moggs andOrphamides, EMBO Reports 2: 775-781 (2001), Hall, et al., Journal ofBiological Chemistry 276: 36869-36872 (2001)].

[0006] A less well-characterized means by which estrogens can affectcells is through a so-called membrane receptor. The existence of such areceptor is controversial, but it has been well documented thatestrogens can elicit very rapid non-genomic responses from cells. Themolecular entity responsible for transducing these effects has not beendefinitively isolated, but there is evidence to suggest it is at leastrelated to the nuclear forms of the estrogen receptors [Levin, Journalof Applied Physiology 91: 1860-1867 (2001), Levin, Trends inEndocrinology & Metabolism 10: 374-377 (1999)].

[0007] Two estrogen receptors have been discovered to date. The firstestrogen receptor was cloned about 15 years ago and is now referred toas ERα [Green, et al., Nature 320: 134-9 (1986)]. The second form of theestrogen receptor was found comparatively recently and is called ERβ[Kuiper, et al., Proceedings of the National Academy of Sciences of theUnited States of America 93: 5925-5930 (1996)]. Early work on ERβfocused on defining its affinity for a variety of ligands and indeed,some differences with ERα were seen. The tissue distribution of ERβ hasbeen well mapped in the rodent and it is not coincident with ERα.Tissues such as the mouse and rat uterus express predominantly ERα,whereas the mouse and rat lung express predominantly ERβ [Couse, et al.,Endocrinology 138: 4613-4621 (1997), Kuiper, et al., Endocrinology 138:863-870 (1997)]. Even within the same organ, the distribution of ERα andERβ can be compartmentalized. For example, in the mouse ovary, ERβ ishighly expressed in the granulosa cells and ERα is restricted to thethecal and stromal cells [Sar and Welsch, Endocrinology 140: 963-971(1999), Fitzpatrick, et al., Endocrinology 140: 2581-2591 (1999)].However, there are examples where the receptors are coexpressed andthere is evidence from in vitro studies that ERα and ERβ can formheterodimers [Cowley, et al., Journal of Biological Chemistry 272:19858-19862 (1997)].

[0008] A large number of compounds have been described that either mimicor block the activity of 17β-estradiol. Compounds having roughly thesame biological effects as 17β-estradiol, the most potent endogenousestrogen, are referred to as “estrogen receptor agonists”. Those which,when given in combination with 17β-estradiol, block its effects arecalled “estrogen receptor antagonists”. In reality there is a continuumbetween estrogen receptor agonist and estrogen receptor antagonistactivity and indeed some compounds behave as estrogen receptor agonistsin some tissues and estrogen receptor antagonists in others. Thesecompounds with mixed activity are called selective estrogen receptormodulators (SERMS) and are therapeutically useful agents (e.g. EVISTA)[McDonnell, Journal of the Society for Gynecologic Investigation 7:S10-S15 (2000), Goldstein, et al., Human Reproduction Update 6: 212-224(2000)]. The precise reason why the same compound can have cell-specificeffects has not been elucidated, but the differences in receptorconformation and/or in the milieu of coregulatory proteins have beensuggested.

[0009] It has been known for some time that estrogen receptors adoptdifferent conformations when binding ligands. However, the consequenceand subtlety of these changes has been only recently revealed. The threedimensional structures of ERα and ERβ have been solved byco-crystallization with various ligands and clearly show therepositioning of helix 12 in the presence of an estrogen receptorantagonist which sterically hinders the protein sequences required forreceptor-coregulatory protein interaction [Pike, et al., Embo 18:4608-4618 (1999), Shiau, et al., Cell 95: 927-937 (1998)]. In addition,the technique of phage display has been used to identify peptides thatinteract with estrogen receptors in the presence of different ligands[Paige, et al., Proceedings of the National Academy of Sciences of theUnited States of America 96: 3999-4004 (1999)]. For example, a peptidewas identified that distinguished between ERα bound to the full estrogenreceptor agonists 17β-estradiol and diethylstilbesterol. A differentpeptide was shown to distinguish between clomiphene bound to ERα andERβ. These data indicate that each ligand potentially places thereceptor in a unique and unpredictable conformation that is likely tohave distinct biological activities.

[0010] As mentioned above, estrogens affect a panoply of biologicalprocesses. In addition, where gender differences have been described(e.g. disease frequencies, responses to challenge, etc), it is possiblethat the explanation involves the difference in estrogen levels betweenmales and females.

DESCRIPTION OF THE INVENTION

[0011] This invention provides estrogenic compound of formula I havingthe structure,

[0012] wherein

[0013] R₁, R₂, R₃, and R₄ are each, independently, selected fromhydrogen, hydroxyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbonatoms, or halogen;

[0014] R₅, R₆, R₇, R₈, R₉, and R₁₀, are each, independently, hydrogen,alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7carbon atoms, halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, phenyl, ora 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selectedfrom O, N or S; wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈,R₉, or R₁₀ may be optionally substituted with hydroxyl, —CN, halogen,trifluroalkyl, trifluoroalkoxy, —NO₂, or phenyl; wherein the phenylmoiety of R₅, R₆, R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, ortri-subsitituted with alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbonatoms, halogen, hydroxyl, alkoxy of 1-6 carbon atoms, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;

[0015] with the proviso that at least one of R₁, R₂, R₃, R₄, R₇, R₈, R₉,or R₁₀ is hydroxyl, or a pharmaceutically acceptable salt thereof.

[0016] Pharmaceutically acceptable salts can be formed from organic andinorganic acids, for example, acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable aids when a compound ofthis invention contains a basic moiety. Salts may also be formed fromorganic and inorganic bases, such as alkali metal salts (for example,sodium, lithium, or potassium) alkaline earth metal salts, ammoniumsalts, alkylammonium salts containing 1-6 carbon atoms ordialkylammonium salts containing 1-6 carbon atoms in each alkyl group,and trialkylammonium salts containing 1-6 carbon atoms in each alkylgroup, when a compound of this invention contains an acidic moiety.

[0017] The terms alkyl and alkenyl include both branched and straightchain moieties. Examples include methyl, ethyl, propyl, butyl,isopropyl, sec-butyl, tert-butyl, vinyl, allyl, 1-methyl vinyl, and thelike. When alkyl or alkenyl moieties are substituted, they may typicallybe mono-, di-, tri- or persubstituted. Examples for a halogensubstituent include 1-bromo vinyl, 1-fluoro vinyl, 1,2-difluoro vinyl,2,2-difluorovinyl, 1,2,2-trifluorovinyl, 1,2-dibromo ethane, 1,2difluoro ethane, 1-fluoro-2-bromo ethane, CF₂CF₃, CF₂CF₂CF₃, and thelike. The term halogen includes bromine, chlorine, fluorine, and iodine.

[0018] Preferred 5-6 membered heterocyclic rings include furan,thiophene, pyrrole, isopyrrole, pyrazole, imidazole, triazole, dithiole,oxathiole, isoxazole, oxazole, thiazole, isothiazolem oxadiazole,furazan, oxatriazole, dioxazole, oxathiazole, tetrazole, pyran,pyridine, pyridazine, pyrimidine, pyrazine, triazine, oxazine,oxathiazine, or oxadiazine. It is more preferred that the heterocyclicring is furan, thiophene, or pyridine.

[0019] As used in accordance with this invention, the term “providing,”with respect to providing a compound or substance covered by thisinvention, means either directly administering such a compound orsubstance, or administering a prodrug, derivative, or analog which willform the effective amount of the compound or substance within the body.

[0020] Of the compounds of this invention, it is preferred that thecompound of formula I has the structure

[0021] wherein

[0022] R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen;

[0023] R₅, R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkylof 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbonatoms, halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;

[0024] with the proviso that at least one of R₅ or R₉ is not hydrogen,or a pharmaceutically acceptable salt thereof.

[0025] It is more preferred that the compound of formula I has thestructure having the structure

[0026] and still more preferred that the 5 or 6-membered heterocyclicring having 1 to 4 heteroatoms selected from O, N or S is furan,thiophene, or pyridine. It is yet more preferred that R₅, R₆, R₇, R₈,and R₉ are each, independently, hydrogen, halogen, —CN, or alkynyl of2-7 carbon atoms.

[0027] The reagents used in the preparation of the compounds of thisinvention can be either commercially obtained or can be prepared bystandard procedures described in the literature.

[0028] The preparation of several representative examples of thisinvention are described in the following Schemes 1-15.

[0029] Standard pharmacological test procedures are readily available todetermine the activity profile of a given test compound. The followingbriefly summarizes several representative test procedures and mayinclude data for representative compounds of the invention. All assays,except the radioligand binding assay, can be used to detect estrogenreceptor agonist or antagonist activity of compounds. In general,estrogen receptor agonist activity is measured by comparing the activityof the compound to a reference estrogen (e.g. 17β-estradiol,17α-ethinyl,17β-estradiol, estrone, diethylstilbesterol etc). Estrogenreceptor antagonist activity is generally measured by co-treating thetest compound with the reference estrogen and comparing the result tothat obtained with the reference estrogen alone. Standardpharmacological test procedures for SERMs are also provided in U.S. Pat.Nos. 4,418,068 and 5,998,402 which are hereby incorporated by reference.

[0030] Evaluation of Binding Affinities to ERα and ERβ

[0031] Representative examples of the invention were evaluated for theirability to compete with 17β-estradiol for both ERα and ERβ in aconventional radioligand binding assay. This test procedure provides themethodology for one to determine the relative binding affinities for theERα or ERβ recptors. The procedure used is briefly described below.

[0032] Preparation of receptor extracts for characterization of bindingselectivity. The ligand binding domains, conveniently defined here asall sequence downstream of the DNA binding domain, were obtained by PCRusing full length cDNA as templates and primers that containedappropriate restriction sites for subcloning while maintaining theappropriate reading frame for expression. These templates containedamino acids M₂₅₀-V₅₉₅ of human ERα [Green, et al., Nature 320: 134-9(1986)] and M₂₁₄-Q₅₃₀ of human ERβ [Ogawa, et al., Biochemical &Biophysical Research Communications 243: 122-6 (1998)]. Human ERβ wascloned into pET15b (Novagen, Madison Wis.) as a Nco1-BamH1 fragmentbearing a C-terminal Flag tag. Human ERα was cloned as for human ERβexcept that an N-terminal His tag was added. The sequences of allconstructs used were verified by complete sequencing of both strands.

[0033] BL21(DE3) cells were used to express the human proteins.Typically a 10 mL overnight culture was used to inoculate a 1 L cultureof LB medium containing 100 μg/mL of ampicillin. After incubationovernight at 37° C., IPTG was added to a final concentration of 1 mM andincubation proceeded at 25° C. for 2 hours. Cells were harvested bycentrifugation (1500×g), and the pellets washed with and resuspended in100 mL of 50 mM Tris-Cl (pH 7.4), 150 mM NaCl. Cells were lysed bypassing twice through a French press at 12000 psi. The lysate wasclarified by centrifugation at 12,000×g for 30 minutes at 4° C. andstored at −70° C.

[0034] Evaluation of extracts for specific [³H]-estradiol binding.Dulbecco's phosphate buffered saline (Gibco, 1×final concentration)supplemented with 1 mM EDTA was used as the assay buffer. To optimizethe amount of receptor to use in the assay, [³H]-17β-estradiol (NewEngland Nuclear; final concentration=2 nM)±0.6 μM diethlystilbestrol and100 μL of various dilutions of the E. coli lysate were added to eachwell of a high binding masked microtiter plate (EG&G Wallac). The finalassay volume was 120 μL and the concentration of DMSO was ≦1%. Afterincubation at room temperature for 5-18 hours, unbound material wasaspirated and the plate washed three times with approximately 300 μL ofassay buffer. After washing, 135 μL of scintillation cocktail (OptiphaseSupermix, EG&G Wallac) was added to the wells, and the plate was sealedand agitated for at least 5 minutes to mix scintillant with residualwash buffer. Bound radioactivity was evaluated by liquid scintillationcounting (EG&G Wallac Microbeta Plus).

[0035] After determining the dilution of each receptor preparation thatprovided maximum specific binding, the assay was further optimized byestimating the IC₅₀ of unlabelled 17β-estradiol using various dilutionsof the receptor preparation. A final working dilution for each receptorpreparation was chosen for which the IC₅₀ of unlabelled 17β-estradiolwas 2-4 nM.

[0036] Ligand binding competition test procedure. Test compounds wereinitially solubilized in DMSO and the final concentration of DMSO in thebinding assay was ≦1%. Eight dilutions of each test compound were usedas an unlabelled competitor for [³H]-17β-estradiol. Typically, a set ofcompound dilutions would be tested simultaneously on human ERα and ERβ.The results were plotted as measured DPM vs. concentration of testcompound. For dose-response curve fitting, a four parameter logisticmodel on the transformed, weighted data was fit and the IC₅₀ was definedas the concentration of compound decreasing maximum [³H]-estradiolbinding by 50%.

[0037] Binding affinities for ERα and ERβ (as measured by IC₅₀) forrepresentative examples of the invention are shown in Table (1). TABLE 1ER binding affinities of representative compounds of the inventionExample ER-β IC₅₀ (nM) ER-α IC₅₀ (nM) 1a 0.054 0.280 1b 0.570 3.140 1c0.527 3.405 1d 0.006 0.022 1e 0.0175 0.180 1f 0.245 0.638 1g 0.374 1.3451h 0.030 0.230 1i 0.519 1.360 1j 0.242 2.120 1k 0.006 0.092 1l 0.0110.107 1m 0.468 1.785 1n 1.360 3.070 1o 0.0127 0.266 1p 0.0025 0.091 1q0.114 0.884 1r 0.007 0.077 1s 0.081 1.402 1t 0.657 1.720 1u 0.017 0.2821v 0.004 0.143 1w 0.032 0.356 1x 0.206 0.802 1y 0.013 0.140 1z 0.00950.039 1aa 0.027 0.074 1ab 0.001 0.006 1ac 0.0032 0.0032 1ad 0.0020 0.0241ae 0.0027 0.018 1af 0.002 0.008 1ag 0.0012 0.058 1ah 0.0011 0.131 1ai0.0025 0.038 1aj 0.0016 0.022 1ak 0.0015 0.021 1al 0.0011 0.040 1am0.0025 0.125 1an 0.0035 0.029 1ao 0.0016 0.012 1ap 0.002 0.029 1aq 0.0020.017 1ar 0.004 0.052 1as 0.0085 0.043 1at 0.010 0.160 1au 0.0023 0.1051av 0.0028 0.208 1aw 0.006 0.109 1ax 0.011 0.299 1ay 0.0084 0.092 1az0.058 0.548 1ba 0.011 0.519 1bb 0.0095 0.095

[0038] The results obtained in the standard pharmacologic test proceduredescribed above demonstrate that the compounds of this invention bindboth subtypes of the estrogen receptor. The IC₅₀s are generally lowerfor ERβ, indicating these compounds are preferentially ERβ selectiveligands, but are still considered active at ERα. Compounds of thisinvention will exhibit a range of activity based, at least partially, ontheir receptor affinity selectivity profiles. Since the compounds of theinvention bind ER-β with higher affinity than ER-α, they will be usefulin treating or inhibiting diseases that can be modulated via ER-β.Additionally, since each receptor ligand complex is unique and thus itsinteraction with various coregulatory proteins is unique, compounds ofthis invention will display different and unpredictable activitiesdepending on cellular context. For example, in some cell-types, it ispossible for a compound to behave as an estrogen receptor agonist whilein other tissues, an estrogen receptor antagonist. Compounds with suchactivity have sometimes been referred to as SERMs (Selective EstrogenReceptor Modulators). Unlike many estrogens, however, many of the SERMsdo not cause increases in uterine wet weight. These compounds areantiestrogenic in the uterus and can completely antagonize the trophiceffects of estrogen receptor agonists in uterine tissue. Thesecompounds, however, act as estrogen receptor agonists in the bone,cardiovascular, and central nervous systems. Due to this tissueselective nature of these compounds, they are useful in treating orinhibiting in a mammal disease states or syndromes which are caused orassociated with an estrogen deficiency (in certain tissues such as boneor cardiovascular) or an excess of estrogen (in the uterus or mammaryglands). In addition, compounds of this invention also have thepotential to behave as estrogen receptor agonists on one receptor typewhile behaving as estrogen receptor antagonists on the other. Forexample, it has been demonstrated that compounds can be antagonize theaction of 17β-estradiol via ERβ while exhibiting estrogen receptoragonist activity with ERα [Sun, et al., Endocrinology 140: 800-804(1999)]. Such ERSAA (Estrogen Receptor Selective Agonist Antagonist)activity provides for pharmacologically distinct estrogenic activitywithin this series of compounds

[0039] Regulation of Metallothionein-II mRNA

[0040] Estrogens acting through ERβ, but not ERα can upregulatemetallothionein II mRNA levels in Saos-2 cells as described by Harris[Endocrinology 142: 645-652 (2001)]. Results from this test procedurecan be combined with results from the test procedure described below(ERE reporter test procedure) to generate a selectivity profile forcompounds of this invention (see also WO 00/37681). Data forrepresentative compounds of the invention are shown in Table (2). TABLE2 Regulation of metallothionein-II mRNA in Saos-2 cells Example 1e 17.0Example 1l 5.5 Example 1o 5.7 Example 1p 6.0 Example 1s 4.9

[0041] Evaluation of Test Compound Using an ERE-Reporter Test Procedurein MCF-7 Breast Cancer Cells

[0042] Stock solutions of test compounds (usually 0.1 M) are prepared inDMSO and then diluted 10 to 100-fold with DMSO to make working solutionsof 1 or 10 mM. The DMSO stocks are stored at either 4° C. (0.1 M) or−20° C. (<0.1M). MCF-7 cells are passaged twice a week with growthmedium [D-MEM/F-12 medium containing 10% (v/v) heat-inactivated fetalbovine serum, 1% (v/v) Penicillin-Streptomycin, and 2 mM glutaMax-1].The cells are maintained in vented flasks at 37° C. inside a 5% CO₂/95%humidified air incubator. One day prior to treatment, the cells areplated with growth medium at 25,000 cells/well into 96 well plates andincubated at 37° C. overnight.

[0043] The cells are infected for 2 hr at 37° C. with 50 μl/well of a1:10 dilution of adenovirus 5-ERE-tk-luciferase in experimental medium[phenol red-free D-MEM/F-12 medium containing 10% (v/v) heat-inactivedcharcoal-stripped fetal bovine serum, 1% (v/v) Penicillin-Streptomycin,2 mM glutaMax-1, 1 mM sodium pyruvate]. The wells are then washed oncewith 150 μl of experimental medium. Finally, the cells are treated for24 hr at 37° C. in replicates of 8 wells/treatment with 150 μl/well ofvehicle (≦0.1% v/v DMSO) or compound that is diluted ≧1000-fold intoexperimental medium.

[0044] Initial screening of test compounds is done at a single dose of 1μM that is tested alone (estrogen receptor agonist mode) or incombination with 0.1 nM 17β-estradiol (EC₈₀; estrogen receptorantagonist mode). Each 96 well plate also includes a vehicle controlgroup (0.1% v/v DMSO) and an estrogen receptor agonist control group(either 0.1 or 1 nM 17β-estradiol). Dose-response experiments areperformed in either the estrogen receptor agonist and/or estrogenreceptor antagonist modes on active compounds in log increases from10⁻¹⁴ to 10⁻⁵ M. From these dose-response curves, EC50 and IC₅₀ values,respectively, are generated. The final well in each treatment groupcontains 5 μl of 3×10⁻⁵ M ICI-182,780 (10⁻⁶ M final concentration) as anestrogen receptor antagonist control.

[0045] After treatment, the cells are lysed on a shaker for 15 min with25 μl/well of 1×cell culture lysis reagent (Promega Corporation). Thecell lysates (20 μl) are transferred to a 96 well luminometer plate, andluciferase activity is measured in a MicroLumat LB 96 P luminometer (EG& G Berthold) using 100 μl/well of luciferase substrate (PromegaCorporation). Prior to the injection of substrate, a 1 second backgroundmeasurement is made for each well. Following the injection of substrate,luciferase activity is measured for 10 seconds after a 1 second delay.The data are transferred from the luminometer to a Macintosh personalcomputer and analyzed using the JMP software (SAS Institute); thisprogram subtracts the background reading from the luciferase measurementfor each well and then determines the mean and standard deviation ofeach treatment.

[0046] The luciferase data are transformed by logarithms, and the HuberM-estimator is used to down-weight the outlying transformedobservations. The JMP software is used to analyze the transformed andweighted data for one-way ANOVA (Dunnett's test). The compoundtreatments are compared to the vehicle control results in the estrogenreceptor agonist mode, or the positive estrogen receptor agonist controlresults (0.1 nM 17β-estradiol) in the estrogen receptor antagonist mode.For the initial single dose experiment, if the compound treatmentresults are significantly different from the appropriate control(p<0.05), then the results are reported as the percent relative to the17β-estradiol control [i.e., ((compound−vehicle control)/(17β-estradiolcontrol−vehicle control))×100]. The JMP software is also used todetermine the EC₅₀ and/or IC₅₀ values from the non-linear dose-responsecurves.

[0047] Evaluation of Uterotrophic Activity

[0048] Uterotrophic activity of a test compound can be measuredaccording to the following standard pharmacological test procedures.

[0049] Procedure 1: Sexually immature (18 days of age) Sprague-Dawleyrats were obtained from Taconic and provided unrestricted access to acasein-based diet (Purina Mills 5K96C) and water. On day 19, 20 and 21the rats were dosed subcutaneously with 17α-ethinyl-17β-estradiol (0.06μg/rat/day), test compound or vehicle (50% DMSO/50% Dulbecco's PBS). Toassess estrogen receptor antagonist, compounds were coadministered with17α-ethinyl-17β-estradiol (0.06 μg/rat/day). There were six rats/groupand they were euthanized approximately 24 hours after the last injectionby CO₂ asphyxiation and pneumothorax. Uteri were removed and weighedafter trimming associated fat and expressing any internal fluid. Atissue sample can also be snap frozen for analysis of gene expression(e.g. complement factor 3 mRNA). Results obtained from representativecompounds of the invention are shown in Table (3). TABLE 3 Evaluation ofselected compounds in a rat uterotrophic Test Procedure. mean uterineweight Compound (mg) ± SEM Vehicle 21.4 ± 1.6 17α ethinyl-17β-estradiol(0.06 μg/rat/day) 85.5 ± 3.1 Example 1 av (2 mg/rat/day) 23.3 ± 1.3Example 1 av (2 mg/rat/day) + 17α-ethinyl- 81.9 ± 4.2 17β-estradiol(0.06 μg/rat/day)

[0050] Procedure 2: Sexually immature (18 days of age) 129 SvE mice wereobtained from Taconic and provided unrestricted access to a casein-baseddiet (Purina Mills 5K96C) and water. On day 22, 23, 24 and 25 the micewere dosed subcutaneously with compound or vehicle (corn oil). Therewere six mice/group and they are euthanized approximately 6 hours afterthe last injection by CO₂ asphyxiation and pneumothorax. Uteri wereremoved and weighed after trimming associated fat and expressing anyinternal fluid. The following results (Table (4)) were obtained forrepresentative compounds from the invention. TABLE 4 Evaluation ofselected compounds in a mouse uterotrophic Test Procedure. mean uterineweight Compound (mg) ± SEM Vehicle 10.3 ± 0.8 17β-estradiol (50mg/kg/day) 45.3 ± 1.9 Example 1av (50 mg/kg/day) 12.6 ± 0.8

[0051] Evaluation of Osteoporosis and Lipid Modulation(Cardioprotection)

[0052] Female Sprague-Dawley rats, ovariectomized or sham operated, areobtained 1 day after surgery from Taconic Farms (weight range 240-275g). They are housed 3 or 4 rats/cage in a room on a 12/12 (light/dark)schedule and provided with food (Purina 5K96C rat chow) and water adlibitum. Treatment for all studies begin 1 day after arrival and ratsare dosed 7 days per week as indicated for 6 weeks. A group of agematched sham operated rats not receiving any treatment serve as anintact, estrogen replete control group for each study.

[0053] All test compounds are prepared in a vehicle of 50% DMSO (JTBaker, Phillipsburg, N.J.)/1×Dulbecco's phosphate saline (GibcoBRL,Grand Island, N.Y.) at defined concentrations so that the treatmentvolume is 0.1 mL/100 g body weight. 17β-estradiol is dissolved in cornoil (20 μg/mL) and delivered subcutaneously, 0.1 mL/rat. All dosages areadjusted at three week intervals according to group mean body weightmeasurements, and given subcutaneously.

[0054] Five weeks after the initiation of treatment and one week priorto the termination of the study, each rat is evaluated for bone mineraldensity (BMD). The total and trabecular density of the proximal tibiaare evaluated in anesthetized rats using an XCT-960M (pQCT; StratecMedizintechnik, Pforzheim, Germany). The measurements are performed asfollows: Fifteen minutes prior to scanning, each rat is anesthetizedwith an intraperitoneal injection of 45 mg/kg ketamine, 8.5 mg/kgxylazine, and 1.5 mg/kg acepromazine.

[0055] The right hind limb is passed through a polycarbonate tube with adiameter of 25 mm and taped to an acrylic frame with the ankle joint ata 90° angle and the knee joint at 180°. The polycarbonate tube isaffixed to a sliding platform that maintains it perpendicular to theaperture of the pQCT. The platform is adjusted so that the distal end ofthe femur and the proximal end of the tibia is in the scanning field. Atwo dimensional scout view is run for a length of 10 mm and a lineresolution of 0.2 mm. After the scout view is displayed on the monitor,the proximal end of the tibia is located. The pQCT scan is initiated 3.4mm distal from this point. The pQCT scan is 1 mm thick, has a voxel(three dimensional pixel) size of 0.140 mm, and consists of 145projections through the slice.

[0056] After the pQCT scan is completed, the image is displayed on themonitor. A region of interest including the tibia but excluding thefibula is outlined. The soft tissue is mathematically removed using aniterative algorithm. The density of the remaining bone (total density)is reported in mg/cm³. The outer 55% of the bone is mathematicallypeeled away in a concentric spiral. The density of the remaining bone(Trabecular density) is reported in mg/cm^(3.)

[0057] One week after BMD evaluation the rats are euthanized by CO₂asphyxiation and pneumothorax, and blood is collected for cholesteroldetermination. The uteri are also removed and the weighed after trimmingassociated fat and expressing any luminal fluid. Total cholesterol isdetermined using a Boehringer-Mannheim Hitachi 911 clinical analyzerusing the Cholesterol/HP kit. Statistics were compared using one-wayanalysis of variance with Dunnet's test.

[0058] Evaluation of Antioxidant Activity

[0059] Porcine aortas are obtained from an abattoir, washed, transportedin chilled PBS, and aortic endothelial cells are harvested. To harvestthe cells, the intercostal vessels of the aorta are tied off and one endof the aorta clamped. Fresh, sterile filtered, 0.2% collagenase (SigmaType I) is placed in the vessel and the other end of the vessel thenclamped to form a closed system. The aorta is incubated at 37° C. for15-20 minutes, after which the collagenase solution is collected andcentrifuged for 5 minutes at 2000×g. Each pellet is suspended in 7 mL ofendothelial cell culture medium consisting of phenol red free DMEM/Ham'sF12 media supplemented with charcoal stripped FBS (5%), NuSerum (5%),L-glutamine (4 mM), penicillin-streptomycin (1000 U/ml, 100 μg/ml) andgentamycin (75 μg/ml), seeded in 100 mm petri dish and incubated at 37°C. in 5%CO₂. After 20 minutes, the cells are rinsed with PBS and freshmedium added, this was repeated again at 24 hours. The cells areconfluent after approximately 1 week. The endothelial cells areroutinely fed twice a week and, when confluent, trypsinized and seededat a 1:7 ratio. Cell mediated oxidation of 12.5 μg/mL LDL is allowed toproceed in the presence of the compound to be evaluated (5 μM) for 4hours at 37° C. Results are expressed as the percent inhibition of theoxidative process as measured by the TBARS (thiobarbituric acid reactivesubstances) method for analysis of free aldehydes [Yagi, BiochemicalMedicine 15: 212-6 (1976)].

[0060] Progesterone Receptor mRNA Regulation Standard PharmacologicalTest Procedure

[0061] This test procedure can be used to evaluate the estrogenic orantiestrogenic activity of compounds from this invention [Shughrue, etal., Endocrinology 138: 5476-5484 (1997)]. Data for representativecompounds of the invention are shown in Table (5). TABLE 5 Effect ofrepresentative compounds of the invention on regulation of progesteronemRNA in the preoptic area of the rat brain Progesterone receptor mRNACompound (arbitrary units; mean ± stdev) Vehicle 55.4 ± 9.417β-estradiol (30 μg/kg) 557.1 ± 80.6 Example 1av (10 mg/kg)  33.7 ±20.6

[0062] Rat Hot Flush Test Procedure

[0063] The effect of test compounds on hot flushes can be evaluated in astandard pharmacological test procedure which measures the ability of atest compound to blunt the increase in tail skin temperature whichoccurs as morphine-addicted rats are acutely withdrawn from the drugusing naloxone [Merchenthaler, et al., Maturitas 30: 307-16 (1998)]. Itcan also be used to detect estrogen receptor antagonist activity byco-dosing test compound with the reference estrogen.

[0064] Evaluation of Vasomotor Function in Isolated Rat Aortic Rings

[0065] Sprague-Dawley rats (240-260 grams) are divided into 4 groups:

[0066] 1. Normal non-ovariectomized (intact)

[0067] 2. Ovariectomized (ovex) vehicle treated

[0068] 3. Ovariectomized 17β-estradiol treated (1 mg/kg/day)

[0069] 4. Ovariectomized animals treated with test compound (variousdoses)

[0070] Animals are ovariectomized approximately 3 weeks prior totreatment. Each animal receives either 17-β estradiol sulfate (1mg/kg/day) or test compound suspended in distilled, deionized water with1% tween-80 by gastric gavage. Vehicle treated animals received anappropriate volume of the vehicle used in the drug treated groups.

[0071] Animals are euthanized by CO₂ inhalation and exsanguination.Thoracic aortae are rapidly removed and placed in 37° C. physiologicalsolution with the following composition (mM): NaCl (54.7), KCl (5.0),NaHCO₃ (25.0), MgCl₂ 2H₂O (2.5), D-glucose (11.8) and CaCl₂ (0.2) gassedwith CO₂—O₂, 95%/5% for a final pH of 7.4. The advantitia is removedfrom the outer surface and the vessel is cut into 2-3 mm wide rings.Rings are suspended in a 10 mL tissue bath with one end attached to thebottom of the bath and the other to a force transducer. A restingtension of 1 gram is placed on the rings. Rings are equilibrated for 1hour, signals are acquired and analyzed.

[0072] After equilibration, the rings are exposed to increasingconcentrations of phenylephrine (10⁻⁸ to 10⁻⁴ M) and the tensionrecorded. Baths are then rinsed 3 times with fresh buffer. Afterwashout, 200 mM L-NAME is added to the tissue bath and equilibrated for30 minutes. The phenylephrine concentration response curve is thenrepeated.

[0073] Evaluation of Cardioprotective Activity

[0074] Apolipoprotein E-deficient C57/B1J (apo E KO) mice are obtainedfrom Taconic Farms. All animal procedures are performed under strictcompliance to IACUC guidelines. Ovariectomized female apo E KO mice, 4-7weeks of age, are housed in shoe-box cages and were allowed free accessto food and water. The animals are randomized by weight into groups(n=12-15 mice per group). The animals are dosed with test compounds orestrogen (17β-estradiol sulfate at 1 mg/kg/day) in the diet using aPrecise-dosing Protocol, where the amount of diet consumed is measuredweekly, and the dose adjusted accordingly, based on animal weight. Thediet used is a Western-style diet (57U5) that is prepared by Purina andcontains 0.50% cholesterol, 20% lard and 25 IU/KG Vitamin E. The animalsare dosed/fed using this paradigm for a period of 12 weeks. Controlanimals are fed the Western-style diet and receive no compound. At theend of the study period, the animals are euthanized and plasma samplesobtained. The hearts are perfused in situ, first with saline and thenwith neutral buffered 10% formalin solution.

[0075] For the determination of plasma lipids and lipoproteins, totalcholesterol and triglycerides are determined using enzymatic methodswith commercially available kits from Boehringer Mannheim and WakoBiochemicals, respectively and analyzed using the Boehringer MannheimHitachii 911 Analyzer. Separation and quantification of plasmalipoproteins were performed using FPLC size fractionation. Briefly,50-100 mL of serum is filtered and injected into Superose 12 andSuperose 6 columns connected in series and eluted at a constant flowrate with 1 mM sodium EDTA and 0.15 M NaCl. Areas of each curverepresenting VLDL, LDL and HDL are integrated using Waters Millennium™software, and each lipoprotein fraction is quantified by multiplying theTotal Cholesterol value by the relative percent area of each respectivechromatogram peak.

[0076] For the quantification of aortic atherosclerosis, the aortas arecarefully isolated and placed in formalin fixative for 48-72 hoursbefore handling. Atherosclerotic lesions are identified using Oil Red Ostaining. The vessels are briefly destained, and then imaged using aNikon SMU800 microscope fitted with a Sony 3CCD video camera system inconcert with IMAQ Configuration Utility (National Instrument) as theimage capturing software. The lesions are quantified en face along theaortic arch using a custom threshold utility software package (ColemanTechnologies). Automated lesion assessment is performed on the vesselsusing the threshold function of the program, specifically on the regioncontained within the aortic arch from the proximal edge of thebrachio-cephalic trunk to the distal edge of the left subclavian artery.Aortic atherosclerosis data are expressed as percent lesion involvementstrictly within this defined luminal area.

[0077] Evaluation of Cognition Enhancement

[0078] Ovariectomized rats (n=50) are habituated to an 8-arm radial armmaze for 10-min periods on each of 5 consecutive days. Animals arewater-deprived prior to habituation and testing. A 100 μL aliquot ofwater placed at the ends of each arm serves as reinforcement.Acquisition of a win-shift task in the radial arm maze is accomplishedby allowing the animal to have access to one baited arm. After drinking,the animal exits the arm and re-enters the central compartment, where itnow has access to the previously visited arm or to a novel arm. Acorrect response is recorded when the animal chooses to enter a novelarm. Each animal is given 5 trials per day for 3 days. After the lastacquisition trial, the animals are assigned to one of the following 4groups:

[0079] 1. Negative controls: injected with 10% DMSO/sesame oil vehicleonce daily for 6 days (1 mukg, SC)

[0080] 2. Positive controls: injected with 17β-estradiol benzoate for 2days and tested 4 days after the second injection (17β-estradiolbenzoate at 10 μg/0.1 mL per rat)

[0081] 3. Estradiol: 17β-estradiol will be injected daily for 6 days (20μg/kg, SC)

[0082] 4. Test compound: injected daily for 6 days (doses vary).

[0083] All injections will begin after testing on the last day ofacquisition. The last injection for groups 1, 3, and 4 will take place 2hours before testing for working memory.

[0084] The test for working memory is a delayed non-matching-to-sampletask (DNMS) utilizing delays of 15, 30, or 60 seconds. This task is avariation of the acquisition task in which the rat is placed in thecentral arena and allowed to enter one arm as before. A second arm isopened once the rat traverses halfway down the first arm, and again therat is required to choose this arm. When it has traveled halfway downthis second arm, both doors are closed and the delay is instituted. Oncethe delay has expired, both of the original two doors, and a third noveldoor, are opened simultaneously. A correct response is recorded when theanimal travels halfway down the third, novel arm. An incorrect responseis recorded when the animal travels halfway down either the first orsecond arms. Each animal will receive 5 trials at each of the threedelay intervals for a total of 15 trials per subject.

[0085] Evaluation of Effect on Pleurisy

[0086] The ability to reduce the symptoms of experimentally-inducedpleurisy in rats can be evaluated according to the procedure ofCuzzocrea [Endocrinology 141: 1455-63 (2000)].

[0087] Evaluation of Protection Against Glutamate-Induced Cytotoxicity(Neuroprotection)

[0088] The neuroprotective activity of compounds of this invention canbe evaluated in an in vitro standard pharmacological test procedureusing glutamate challenge [Zaulyanov, et al., Cellular & MolecularNeurobiology 19: 705-18 (1999); Prokai, et al., Journal of MedicinalChemistry 44: 110-4 (2001)].

[0089] Evaluation in the Mammary End Bud Test Procedure

[0090] Estrogens are required for full ductal elongation and branchingof the mammary ducts, and the subsequent development of lobulo-alveolarend buds under the influence of progesterone. In this test procedure,the mammotrophic activity of selected compounds of the invention wasevaluated according to the following standard pharmacological testprocedure. Twenty-eight day old Sprague-Dawley rats (Taconic Farms,Germantown, N.Y.) were ovariectomized and rested for nine days. Animalswere housed under a 12-hour light/dark cycle and fed a casein-basedPurina Laboratory Rodent Diet 5K96 (Purina, Richmond, IN) and allowedfree access to water. Rats were then dosed subcutaneously for six dayswith vehicle (50% DMSO (JT Baker, Phillipsburg, N.J.)/50% 1×Dulbecco'sPhosphate buffered saline (GibcoBRL, Grand Island, N.Y.), 17β-estradiol(0.1 mg/kg) or test compound (20 mg/kg). For the final three days, ratswere also dosed subcutaneously with progesterone (30 mg/kg). On theseventh day, rats were euthanised and a mammary fat pad excised. Thisfat pad was analyzed for casein kinase II mRNA as a marker of end budproliferation. Casein kinase II mRNA was anlayzed by real-time RT-PCR.Briefly, RNA was isolated following Trizol (GibcoBRL, Grand Island,N.Y.) according to the manufacture's directions, Samples were treatedwith DNAse I using DNA-free kit (Ambion), and casein kinase II mRNAlevels were measured by real-time RT-PCR using the Taqman Gold procedure(PE Applied Biosystems). A total of 50 ng of RNA was analyzed intriplicate using casein kinase II specific primer pair (5′ primer,CACACGGATGGCGCATACT; 3′ primer, CTCGGGATGCACCATGAAG) and customizedprobe (TAMRA-CGGCACTGGTTTCCCTCACATGCT-FAM). Casein kinase II mRNA levelswere normalized to 18s ribosomal RNA contained within each samplereaction using primers and probe supplied by PE Applied Biosystems. Thefollowing results were obtained for representative compounds of theinvention (Table (6)). TABLE 6 Evaluation of compounds in a ratmammotrophic assay Casein kinase II mRNA/18S rRNA Compound (mean ± SEM)Vehicle 2.66 ± 0.13 Progesterone (30 mg/kg) + 39.0 ± 5.4  17β-estradiol(0.1 mg/kg) Progesterone (30 mg/kg) + 1.06 ± 0.17 Example 1av (20 mg/kg)

[0091] Evaluation in the HLA Rat Standard Pharmacological Test Procedurefor Inflammatory Bowel Disease

[0092] Compounds of the invention can be evaluated in the HLA ratstandard pharmacological test procedure that emulates inflammatory boweldisease in humans. The following briefly describes the procedure usedand results obtained. Male HLA-B27 rats (8-10 weeks old) were obtainedfrom Taconic and provided unrestricted access to food (PMI Lab diet5001) and water. Rats were dosed orally each day for 46 days with eithervehicle (2% tween-80/0.5% mentylcellulose) or Example 1av (10 mg/kg).Stool quality was observed daily and graded according to the followingscale: Diarrhea=3; soft stool=2; normal stool=1. At the end of thestudy, serum was collected and stored at −70° C. A section of colon wasprepared for histological analysis and an additional segment wasanalyzed for myeloperoxidase activity. The following results wereobtained (Table (7)) and show that stool character normalized within 21days of administration of Example 1av. TABLE 7 Stool scores from HLArats treated orally with vehicle or Example 1av for 46 days. Valuereported is the group's average score for the first 26 days of dosing.Day Vehicle Example 1av 1 2.75 2.75 2 3 2.5 3 3 2.25 4 3 2.5 5 3 2.25 63 2.5 7 3 2.5 8 3 2 9 3 2 10 3 1.5 11 3 1.5 12 3 1.5 13 3 1.75 14 3 1.7515 3 1.5 16 3 1.5 17 3 1.25 18 3 1.25 19 3 1.25 20 3 1.25 21 3 1.25 22 31 23 3 1 24 3 1 25 3 1

[0093] For histological analysis, colonic tissue was immersed in 10%neutral buffered formalin. Each specimen of colon was separated intofour samples for evaluation. The formalin-fixed tissues were processedin a Tissue Tek vacuum infiltration processor (Miles, Inc; West Haven,Conn.) for paraffin embedding. The samples were sectioned at 5 μm andthen stained with hematoxylin and eosin (H&E) for blinded histologicevaluations using a scale modified after Boughton-Smith. After thescores were completed the samples were unblinded, and data weretabulated and analyzed by ANOVA linear modeling with multiple meancomparisons. Sections of colonic tissue were evaluated for severaldisease indicators and given relative scores. As shown in Table (8)Example 1av is effective in reducing several measurements of tissueinjury. TABLE 8 Histological scoring of disease severity in the HLA-B27rat model after oral dosing for 46 days with vehicle or Example 1 av.Ulceration Inflammation Lesion depth Fibrosis Group (0-2) (0-3) (0-2)(0-2) Total score Vehicle 1.19 ± 0.69 2.38 ± 0.32  1.0 ± 0.54 0.94 ±0.75 5.50 ± 2.1 Example 1 av 0.44 ± 0.43  1.13 ± 0.43* 0.38 ± 0.43  0.07± 0.13*  2.00 ± 1.14*

[0094] Evaluation in Two Models of Arthritis

[0095] Lewis rat assay of adjuvant-induced arthritis. Sixty, female, 12weeks old, Lewis rats are housed according to standard facilityoperating procedures. They receive a standard regimen of food and waterad libitum. Each animal is identified by a cage card indicating theproject group and animal number. Each rat number is marked by indelibleink marker on the tail. At least 10-21 days before study they areanesthetized and ovariectomized by standard aseptic surgical techniques.

[0096] Freund's Adjuvant-Complete (Sigma Immuno Chemicals, St. Louis,Mo.) is used to induce arthritis, each mL containing 1 mg Mycobacteriumtuberculosis heat killed and dried, 0.85 mL mineral oil and 0.15 mLmannide monooleate Lot No. 084H8800.

[0097] The following are examples of two test procedures. Inhibitiontest procedure: Thirty rats are injected intradermally with 0.1 mL ofFreund's Adjuvant-Complete at the base of the tail. The animals arerandomized to groups of six rats each., Each day, the groups receivevehicle (50% DMSO (JT Baker, Phillipsburg, N.J.)/1×Dulbecco's phosphatesaline (GibcoBRL, Grand Island, N.Y.)) or test compound (administeredsubcutaneously). All rats began treatment on Day 1. Data for Example 1av is shown in Table (9).

[0098] Treatment test procedure: Thirty rats are injected intradermallywith 0.1 mL of Freund's Adjuvant-Complete at the base of the tail. Theanimals are randomized to four groups, each group containing six rats.Each day, the groups receive vehicle (50% DMSO (JT Baker, Phillipsburg,N.J.)/1×Dulbecco's phosphate saline (GibcoBRL, Grand Island, N.Y.)) ortest compound (administered subcutaneously). All rats began treatment onDay 8 after adjuvant injection. Data for Example 1av is shown in Tables(10), (11) and (12).

[0099] Statistical analysis was performed using Abacus Concepts SuperANOVA. (Abacus Concepts, Inc., Berkeley, Calif.). All of the parametersof interest were subjected to Analysis of Variance with Duncan's newmultiple range post hoc testing between groups. Data are expressedthroughout as mean±standard deviation (SD), and differences were deemedsignificant if p<0.05.

[0100] The degree of arthritis severity is monitored daily in terms ofthe following disease indices: Hindpaw erythema, hindpaw swelling,tenderness of the joints, and movements and posture. An integer scale of0 to 3 is used to quantify the level of erythema (0=normal paw, 1=milderythema, 2=moderate erythema, 3=severe erythema) and swelling (0=normalpaw, 1=mild swelling, 2=moderate swelling, 3=severe swelling of the hindpaw). The maximal score per day is 12.

[0101] At the end of the study the rats are euthanized with CO₂,hindlimbs removed at necropsy and fixed in 10% buffered formalin, andthe tarsal joints decalcified and embedded in paraffin. Histologicsections are stained with Hematoxylin and Eosin or Saffranin O—FastGreen stain.

[0102] Slides are coded so that the examiner is blinded to the treatmentgroups. Synovial tissue from tarsal joints is evaluated based onsynovial hyperplasia, inflammatory cell infiltration, and pannusformation [Poole and Coombs, International Archives of Allergy & AppliedImmunology 54: 97-113 (1977)] as outlined below. Category Grade 1.Synovial lining cells a. No change 0 b. Cells enlarged, slightlythickened 1 c. Cells enlarged, increase in numbers, moderatelythickened. 2 No villus present d. Cells enlarged, thickened. Villluspresent 3 2. Fibroplasia a. No change 0 b. Fibroplasia present underlining cells 1 c. Small areas of areolar tissue replaced by fibroustissue 2 d. Replacement of areolar tissue by fibrous tissue 3 3.Inflammatory cells a. Occasionally seen, scattered throughout selection0 b. Cells present in small numbers in or just under lining cell 1 layerand/or around blood vessels. c. Small focal collection of cells may bepresent 2 d. Large numbers of cells present in capsule and in or under 3lining cell layers. Large foci often seen. 4. Pannus a. Not detectable 0b. Detectable 1

[0103] In addition, articular cartilage and bone is evaluated usingMankin's histological grading system [Mankin, et al., Journal of Bone &Joint Surgery—American Volume 53: 523-37 (1971)] as shown below.Category Grade 1. Structure a. Normal 0 b. Surface irregularity 1 c.Pannus and surface irregularity 2 d. Clefts to transitional zone 3 e.Clefts to radial zone 4 f. Clefts to calcified zone 5 g. Completedisorganization 6 2. Cells a. Normal 0 b. Diffuse hypercellularity 1 c.Cloning 2 d. Hypocellularity 3 3. Safranin-O staining a. Normal 0 b.Slight reduction 1 c. Modest reduction 2 d. Severe reduction 3 e. No dyenoted 4 4. Tidemark integrity a. Intact 0 b. Crossed by blood vessels 1

[0104] TABLE 9 Evaluation of joint inflammation of Lewis rats:Inhibition protocol Day Vehicle Example 1av 1 0.00 0.00 2 0.00 0.00 34.50 2.66 4 5.50 1.83 5 9.33 2.66 6 10.50 2.16 7 10.60 2.00 8 11.00 1.669 11.50 2.00 10 11.33 2.00 11 10.83 1.66 12 10.83 1.66 13 11.00 2.16 1411.00 2.00 15 11.00 2.00 16 11.00 1.00 17 10.50 1.33

[0105] TABLE 10 Evaluation of joint inflammation of Lewis rats:Treatment protocol Day Vehicle Example 1av 1 10.83 11.33 2 11.00 10.83 310.83 9.33 4 11.33 8.00 5 11.50 5.83 6 11.50 3.33 7 11.50 3.00 8 11.502.50 9 11.00 2.50 10 11.00 2.50 11 10.66 2.50 12 10.66 2.50 13 10.502.50 14 9.83 2.50 15 8.10 2.00 16 7.35 1.33 17 6.50 1.00

[0106] TABLE 11 Histological scoring of synovitis in the tarsal jointsof Lewis rats (mean ± SD): Treatment protocol Total SynovialInflammatory Synovitis Structure Fibroplasia Cells Pannus Score Group(0-3) (0-3) (0-3) (0-1) (0-10) Vehicle 2.58 ± 0.38 1.75 ± 0.42 2.92 ±0.20 1.00 ± 0.89 8.25 ± 1.57 Example 1 av  1.58 ± 0.38*  0.75 ± 0.42* 1.25 ± 0.42*  0.33 ± 0.61*  3.83 ± 0.93* 10 mg/kg

[0107] TABLE 12 Histological scoring of cartilage change (Mankin scores)in the tarsal joints of Lewis rats (mean ± SD): Treatment protocolSaffranin-O/ Cartilage Fast Green Tidemark Total Cartilage StructureCells Staining Integrity Mankin Score Group (0-6) (0-3) (0-4) (0-1)(0-14) Vehicle 2.83 ± 0.26 2.58 ± 0.38 2.50 ± 0.32 0 7.92 ± 0.74 Example1 av  1.83 ± 0.68*  0.75 ± 0.42*  1.25 ± 0.52* 0  3.83 ± 1.21* 10 mg/kg

[0108] Evaluation in the HLA-B27 Rat model of arthritis. Compounds ofthe invention can be evaluated in the HLA-B27 rat standardpharmacological test procedure which emulates arthritis in humans. Thefollowing briefly describes the procedure used and results obtained.Male HLA-B27 rats were obtained from Taconic and provided unrestrictedaccess to a food (PMI Lab diet 5001) and water. Joint scores andhistology are evaluated as described above for the Lewis rat model ofadjuvant-induced arthritis. Rats (8-10 weeks old) were dosed orally onceper day for forty-six days with either vehicle (2% Tween-80/0.5%methylcellulose) or Example 1av (10 mg/kg) There were 4 rats in eachgroup and the last dose was administered two hours before euthanasia. Asshown in Table (13), joint inflammation was reduced by treatment withExample 1av. The synovitis and Mankin scores (Table (14)) were alsoreduced, but were not statistically different than those ofvehicle-treated rats. TABLE 13 Evaluation of joint inflammation from HLArats treated orally for 46 days with Example 1av Example 1av Day Vehicle(10 mg/kg) 29 2.5 0.5 30 6 0.5 31 5 0.5 32 6.75 1 33 8 1.75 34 8 1.5 358 1 36 6 1.75 37 7.5 1.75 38 6.5 1.5 39 7.5 0.75 40 7.5 0.75 41 6.5 0.542 6.5 1.5 43 6 1.25 44 6.75 1.75 45 5.5 1.25 46 6 0.75

[0109] TABLE 14 Evaluation of joint histology from HLA rats treatedorally for 46 days with Example 1av Compound Synovitis score (mean ± SD)Mankin score (mean ± SD) Vehicle 7.6 ± 3.1 6.5 ± 1.2 Example 1av 5.0 ±2.5 4.5 ± 1.8 (10 mg/kg)

[0110] Evaluation in in vivo Models of Carcinogeneisis

[0111] The ability of compounds of this invention to treat and inhibitvarious malignancies or hyperprolific disorders can be evaluated instandard pharmacological test procedures that are readily available inthe literature, and include the following two procedures.

[0112] Breast cancer. Athymic nu/nu (nude) mice are obtainedovariectomized from Charles River Laboratories (Wilmington, Mass.). Oneday prior to tumor cell injection, animals are implanted withtime-release pellets containing 0.36-1.7 mg 17β-estradiol (60 or 90 dayrelease, Innovative Research of America, Sarasota, Fla.) or a placebo.The pellet is introduced subcutaneously into the intrascapular regionusing a 10-gauge precision trochar. Subsequently, mice are injectedsubcutaneously into the breast tissue with either 1×10⁷ MCF-7 cells or1×10⁷ BG-1 cells. The cells are mixed with an equal volume of matrigel,a basement membrane matrix preparation to enhance tumor establishment.Test compounds can be evaluated either by dosing one day after tumorcell implantation (inhibition regimen) or after tumors have reached acertain size (treatment regimen). Compounds are administered eitherintraperitoneally or orally in a vehicle of 1% tween-80 in saline eachday. Tumor size is evaluated every three or seven days.

[0113] Colon cancer. The ability to treat or inhibit colon cancer can beevaluated in the test procedure of Smirnoff [Oncology Research 11:255-64 (1999)].

[0114] Evaluation of Neuroprotection in Two in vivo Test Procedures

[0115] Transient global ischemia in the Mongolian gerbil. The effect oftest compounds on preventing or treating brain injury in response tooxygen deprivation/reperfusion can be measured using the following testprocedure.

[0116] Female Mongolian gerbils (60-80 g; Charles River Laboratories,Kingston, N.Y.) are housed in the Wyeth-Ayerst animal care facility(AAALAC certified) with a 12-hour light, 12-hour dark photoperiod andfree access to tap water and a low-estrogen casein diet (Purina;Richmond, Ind.). After acclimation (3-5 days), gerbils are anesthetizedwith isoflurane (2-3% mixture with O₂), ovariectomized (Day 0).Beginning the following morning (Day 1), gerbils are treatedsubcutaneously each day with either vehicle (10% ETOH/corn oil),17β-estradiol (1 mg/kg, sc) or an experimental compound. On Day 6,gerbils (n=4-5/group) are anesthetized with isoflurane, the commoncarotid arteries visualized via a mid-line neck incision and botharteries simultaneously occluded for 5 minutes with non-traumatic microaneurysm clips. After occlusion, the clips are removed to allow cerebralreperfusion and the neck incision closed with wound clips. All animalsare fasted overnight prior to the global ischemia surgery, a step thatfacilitates consistent ischemic injury. On Day 12, gerbils are exposedto a lethal dose of CO₂, and the brains frozen on dry ice and stored at−80° C. The animal protocols used for these studies are reviewed andapproved by the Radnor/Collegeville Animal Care and Use Committee(RACUC/CACUC) at Wyeth-Ayerst Research.

[0117] The degree of neuronal protection is evaluated by in situhybridization analysis of neurogranin mRNA. Briefly, 20 μm coronalcryostat sections are collected on gelatin-coated slides, dried andstored at −80° C. At the time of processing, the desiccated slide boxesare warmed to room temperature, the slides postfixed in 4%paraformaldehyde, treated with acetic anhydride and then delipidated anddehydrated with chloroform and ethanol. Processed section-mounted slidesare then hybridized with 200 μl (6×10⁶ DPM/slide) of an antisense orsense (control) riboprobe for Neurogranin (³⁵S-UTP-labeled NG-241; bases99-340). in a 50% formamide hybridization mix and incubated overnight at55° C. in a humidified slide chamber without coverslipping. Thefollowing morning, the slides are collected in racks, immersed in 2×SSC(0.3 M NaCl, 0.03 M sodium citrate; pH 7.0)/10 mM DTT, treated withRNase A (20 μg/ml) and washed (2×30 min) at 67° C. in 0.1×SSC to removenonspecific label. After dehydration, the slides are opposed to BioMax(BMR-1; Kodak) X-ray film overnight.

[0118] The level of neurogranin hybridization signal is used toquantitatively assess the degree of neuronal loss in the CA1 regionafter injury and to evaluate the efficacy of 17β-estradiol andexperimental compounds. Neurogranin mRNA is selected for these studiesbecause it is highly expressed in the hippocampal neurons including CA1,but absent in glia and other cell types present in this brain region.Therefore, measurement of the amount of neurogranin mRNA presentrepresents surviving neurons. Relative optical density measurements ofneurogranin hybridization signal are obtained from film autoradiogramswith a computer based image analysis system (C-Imaging Inc., Pittsburgh,Pa.). The results from 6 sections (40 μm apart) per animal are averagedand statistically evaluated. Numerical values are reported as themean±SEM. One-way analysis of variance is used to test for differencesin the level of neurogranin mRNA and all statements of non-difference inthe results section imply that p>0.05.

[0119] Middle cerebral artery occlusion in mice. Neuroprotection can beevaluated according to the test procedures described by Dubal [see,Dubal, et al., Proceedings of the National Academy of Sciences of theUnited States of America 98: 1952-1957 (2001), Dubal, et al., Journal ofNeuroscience 19: 6385-6393 (1999)].

[0120] Ovulation Inhibition Standard Pharmacological Test Procedure

[0121] The test procedure is used to determine whether test compoundscan inhibit or change the timing of ovulation. It can also be used todetermine the number of oocytes ovulated [Lundeen, et al., J SteroidBiochem Mol Biol 78: 137-143 (2001)].

[0122] Based on the results obtained in the standard pharmacologicaltest procedures, the compounds of this invention are estrogen receptormodulators useful in the treatment or inhibition of conditions,disorders, or disease states that are at least partially mediated by anestrogen deficiency or excess, or which may be treated or inhibitedthrough the use of an estrogenic agent. The compounds of this inventionare particularly useful in treating a peri-menopausal, menopausal, orpostmenopausal patient in which the levels of endogenous estrogensproduced are greatly diminished. Menopause is generally defined as thelast natural menstrual period and is characterized by the cessation ofovarian function, leading to the substantial diminution of circulatingestrogen in the bloodstream. As used herein, menopause also includesconditions of decreased estrogen production that may be surgically,chemically, or be caused by a disease state which leads to prematurediminution or cessation of ovarian function.

[0123] The compounds of this invention are also useful in inhibiting ortreating other effects of estrogen deprivation including, hot flushes,vaginal or vulvar atrophy, atrophic vaginitis, vaginal dryness,pruritus, dyspareunia, dysuria, frequent urination, urinaryincontinence, urinary tract infections. Other reproductive tract usesinclude the treatment or inhibition of dysfunctional uterine bleeding.The compounds are also useful in treating or inhibiting endometriosis.

[0124] The compounds of this invention are also active in the brain andare therefore useful for inhibiting or treating Alzheimer's disease,cognitive decline, decreased libido, senile dementia, neurodegenerativedisorders, depression, anxiety, insomnia, schizophrenia, andinfertility. The compounds of this invention are also useful in treatingor inhibiting benign or malignant abnormal tissue growth including,glomerulosclerosis, prostatic hypertrophy, uterine leiomyomas, breastcancer, scleroderma, fibromatosis, endometrial cancer, polycystic ovarysyndrome, endometrial polyps, benign breast disease, adenomyosis,ovarian cancer, melanoma, prostate cancer, cancers of the colon, CNScancers, such as glioma or astioblastomia.

[0125] The compounds of this invention are cardioprotective and areantioxidants, and are useful in lowering cholesterol, triglycerides,Lp(a), and LDL levels; inhibiting or treating hypercholesteremia,hyperlipidemia, cardiovascular disease, atherosclerosis, peripheralvascular disease, restenosis, and vasospasm, and inhibiting vascularwall damage from cellular events leading toward immune mediated vasculardamage. The compounds of this invention are also useful in treatingdisorders associated with inflammation or autoimmune diseases, includinginflammatory bowel disease (Crohn's disease, ulcerative colitis,indeterminate colitis), arthritis (rheumatoid arthritis,spondyloarthropathies, osteoarthritis), pleurisy, ischemia/reperfusioninjury (e.g. stroke, transplant rejection, myocardial infarction, etc.),asthma, giant cell arteritis, prostatitis interstitial cystitis,uveitis, psoriasis, multiple sclerosis, systemic lupus erythematosus andsepsis.

[0126] The compounds of this invention are also useful in treating orinhibiting ocular disorders including cataracts, uveitis, and maculardegeneration and in treating skin conditions such as aging, alopecia,and acne.

[0127] The compounds of this invention are also useful in treating orinhibiting metabolic disorders such as type-II diabetes, of lipidmetabolism, appetite (e.g. anorexia nervosa and bulimia).

[0128] Compounds in this invention are also useful in treating orinhibiting bleeding disorders such as hereditary hemorrhagictelangiectasia, dysfunctional uterine bleeding, and combatinghemorrhagic shock.

[0129] The compounds of this invention are useful in disease stateswhere amenorrhea is advantageous, such as leukemia, endometrialablations, chronic renal or hepatic disease or coagulation diseases ordisorders.

[0130] The compounds of this invention can be used as a contraceptiveagent, particularly when combined with a progestin.

[0131] When administered for the treatment or inhibition of a particulardisease state or disorder, it is understood that the effective dosagemay vary depending upon the particular compound utilized, the mode ofadministration, the condition, and severity thereof, of the conditionbeing treated, as well as the various physical factors related to theindividual being treated. Effective administration of the compounds ofthis invention may be given at an oral dose of from about 0.1 mg/day toabout 1,000 mg/day. Preferably, administration will be from about 10mg/day to about 600 mg/day, more preferably from about 50 mg/day toabout 600 mg/day, in a single dose or in two or more divided doses. Theprojected daily dosages are expected to vary with route ofadministration.

[0132] Such doses may be administered in any manner useful in directingthe active compounds herein to the recipient's bloodstream, includingorally, via implants, parentally (including intravenous,intraperitoneal, intraarticularly and subcutaneous injections),rectally, intranasally, topically, ocularly (via eye drops), vaginally,and transdermally.

[0133] Oral formulations containing the active compounds of thisinvention may comprise any conventionally used oral forms, includingtablets, capsules, buccal forms, troches, lozenges and oral liquids,suspensions or solutions. Capsules may contain mixtures of the activecompound(s) with inert fillers and/or diluents such as thepharmaceutically acceptable starches (e.g. corn, potato or tapiocastarch), sugars, artificial sweetening agents, powdered celluloses, suchas crystalline and microcrystalline celluloses, flours, gelatins, gums,etc. Useful tablet formulations may be made by conventional compression,wet granulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants, surfacemodifying agents (including surfactants), suspending or stabilizingagents, including, but not limited to, magnesium stearate, stearic acid,talc, sodium lauryl sulfate, microcrystalline cellulose,carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginicacid, acacia gum, xanthan gum, sodium citrate, complex silicates,calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalciumphosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride,talc, dry starches and powdered sugar. Preferred surface modifyingagents include nonionic and anionic surface modifying agents.Representative examples of surface modifying agents include, but are notlimited to, poloxamer 188, benzalkonium chloride, calcium stearate,cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters,colloidol silicon dioxide, phosphates, sodium dodecylsulfate, magnesiumaluminum silicate, and triethanolamine. Oral formulations herein mayutilize standard delay or time release formulations to alter theabsorption of the active compound(s). The oral formulation may alsoconsist of administering the active ingredient in water or a fruitjuice, containing appropriate solubilizers or emulsifiers as needed.

[0134] In some cases it may be desirable to administer the compoundsdirectly to the airways in the form of an aerosol.

[0135] The compounds of this invention may also be administeredparenterally or intraperitoneally. Solutions or suspensions of theseactive compounds as a free base or pharmacologically acceptable salt canbe prepared in water suitably mixed with a surfactant such ashydroxy-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto inhibit the growth of microorganisms.

[0136] The pharmaceutical forms suitable for injectable use includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0137] For the purposes of this disclosure, transdermal administrationsare understood to include all administrations across the surface of thebody and the inner linings of bodily passages including epithelial andmucosal tissues. Such administrations may be carried out using thepresent compounds, or pharmaceutically acceptable salts thereof, inlotions, creams, foams, patches, suspensions, solutions, andsuppositories (rectal and vaginal).

[0138] Transdermal administration may be accomplished through the use ofa transdermal patch containing the active compound and a carrier that isinert to the active compound, is non toxic to the skin, and allowsdelivery of the agent for systemic absorption into the blood stream viathe skin. The carrier may take any number of forms such as creams andointments, pastes, gels, and occlusive devices. The creams and ointmentsmay be viscous liquid or semisolid emulsions of either the oil-in-wateror water-in-oil type. Pastes comprised of absorptive powders dispersedin petroleum or hydrophilic petroleum containing the active ingredientmay also be suitable. A variety of occlusive devices may be used torelease the active ingredient into the blood stream such as asemi-permeable membrane covering a reservoir containing the activeingredient with or without a carrier, or a matrix containing the activeingredient. Other occlusive devices are known in the literature.

[0139] Suppository formulations may be made from traditional materials,including cocoa butter, with or without the addition of waxes to alterthe suppository's melting point, and glycerin. Water soluble suppositorybases, such as polyethylene glycols of various molecular weights, mayalso be used.

[0140] The preparation of representative examples of this invention isdescribed below.

[0141] Synthesis of Compounds in Scheme 1

Intermediate 2 7-Methoxy-2-naphthyl trifluoromethanesulfonate

[0142] To a solution of 7-methoxy-2-naphthol (4.75 g, 27.27 mmol) andpyridine (3.5 mL, 44 mmol) in 200 mL of dichloromethane at 0° C. wasadded trifluoromethanesulfonic anhydride (10.0 g, 35 mmol). The solutionwas allowed to slowly warm to room temperature and stirred overnight.The solution was cooled to 0° C. and stirred with ice water to decomposeexcess anhydride. The mixture was made slightly basic by the addition ofsaturated sodium bicarbonate solution. The resulting layers wereseparated and the aqueous layer was extracted with dichloromethane(2×250 mL). The combined organic layers were washed with water, driedover magnesium sulfate, filtered, and evaporation of the solvent yieldeda red oil which was purified by silica chromatography (5% ethylacetate-hexanes) to yield 8.08 g (97%) of the title compound as a clear,colorless oil. ¹H NMR (DMSO-d₆) δ 3.92 (3H, s), 7.30 (1H, dd, J=2.58 Hz,J=8.93 Hz), 7.42 (1H, dd, J=2.59 Hz, J=8.93 Hz), 7.52 (1H, d, J=2.38Hz), 7.96 (1H, d, J=9.12 Hz), 8.00 (1H, d, J=2.38 Hz), 8.06 (1H, d,J=8.73 Hz); MS (EI)m/z306(M)⁺.

[0143] Anal. for C₁₂H₉F₃O₄S Calc'd: C: 47.06H: 2.96 Found: C: 46.62H:2.84

Intermediate 3 2-Methoxy-7-(4-methoxyphenyl)naphthalene

[0144] Method A

[0145] A mixture of 7-methoxy-2-naphthyl trifluoromethanesulfonate (3.15g, 10.3 mmol), 4-methoxy-phenylboronic acid (2.2 g, 14 mmol) sodiumcarbonate (10 mL of 2N aqueous solution),tetrakis(triphenylphosphine)palladium (0.59 g, 0.05 mmol), and 100 mLethylene glycol dimethyl ether were heated to reflux for 8 hr. Themixture was cooled to room temperature and poured into 100 mL of 1 NNaOH, The mixture was extracted with ethyl acetate (3×250 mL), washedwith brine (2×100 mL), dried over magnesium sulfate, filtered,evaporation of the solvent and purification by silica chromatography(5%-10% ethyl acetate-hexanes) yielded 2.17 g (79%) of the titlecompound as a white solid: mp 154° C.; ¹H NMR (CDCl₃): δ 3.87 (3H, s),3.94 (3H, s), 7.02 (2H, d, J=8.72 Hz), 7.13 (1H, dd, J=2.54 Hz, J=9.09Hz), 7.18 (1H, d, J=2.55 Hz), 7.56 (1H, dd, J=1.82 Hz, J=8.36 Hz), 7.65(2H, d, J=8.72 Hz), 7.74 (1H, d, J=9.09 Hz), 7.81 (1H, d, J=8.36 Hz),7.89 (1H, d, J=1.09 Hz); MS (EI) m/z264 (M).

[0146] Anal. for C₁₈H₁₆O₂: Calc'd: C: 81.79H: 6.10 Found: C: 81.78H:6.17

Intermediate 4 2-Methoxy-7-(3-methoxyphenyl)naphthalene

[0147] The title compound was prepared by reacting 7-methoxy-2-naphthyltrifluoromethanesulfonate (2.20 g, 7.18 mmol) with3-methoxyphenylboronic acid (1.20 g, 7.90 (mmol) according to method Aabove to yield a white solid: mp 58-59° C.;¹H NMR (CDCl₃): δ 3.89 (3H,s), 3.93 (3H, s), 6.91-6.94 (1H, m), 7.15 (1H, dd, J=2.42 Hz, J=8.83Hz), 7.19H, d, J=2.27 Hz), 7.23-7.25 (1H, m), 7.28-7.31 (1H, m),7.37-7.42 (1H, m), 7.59 (1H, dd, J=1.56 Hz, J=8.46 Hz), 7.75 (1H, d,J=8.84 Hz), 7.83 (1H, d, J=8.45 Hz), 7.94 (s1H, s); MS (ESI) m/z265(M+H)⁻.

[0148] Anal.for C₁₈H₁₆O₂: Calc'd C: 81.79H: 6.10 Found: C: 81.61H: 5.99

Intermediate 5 2-Methoxy-7-phenylnaphthalene

[0149] The title compound was prepared by reacting 7-methoxy-2-naphthyltrifluoromethanesulfonate (3.01 g, 9.83 mmol) with phenylboronic acid(1.4 g, 12 mmol) according to method A to yield 1.95 g (85%) of a whitesolid mp 62-64° C.; ¹H NMR (CDCl₃) δ 3.95 (3H, s), 7.15 (1H, dd, J=2.56Hz, J=8.79 Hz), 7.20 (1H, d, J=2.56 Hz), 7.36-7.39 (1H, m), 7.46-7.50(2H, m), 7.60 (1H, dd, J=1.83 Hz, J=8.42 Hz), 7.70-7.73 (2H, m), 7.76(1H, d, J=8.79 Hz), 7.84 (1H, d, J=8.42 Hz), 7.94 (1H, d, J=1.46 Hz); MS(EI) m/z 234 (M)+.

[0150] Anal. for C₁₇H₁₄O 0.1H₂O: Calc'd C: 86.48H: 6.06 Found: C:86.29H: 6.04

EXAMPLE 1a 7-(4-Hydroxyphenyl)-2-naphthol

[0151] Method B

[0152] 2-Methoxy-7-(4-methoxy-phenyl)naphthalene (1.02 g, 3.86 mmol) wasadded to of pyridinium HCl (10 g) at 190° C. The solution was stirredfor 3 hr at 190° C. and cooled to room temperature and stirred with 200mL of 1 N HCl. The resulting suspension was filtered and dissolved ethylacetate (500 mL). The combined organic layers were washed with water(200 mL), dried over magnesium sulfate, filtered, the solvent removedunder vacuum, and the product purified by silica chromatography (40%ethyl acetate-hexanes to yield 0.36 g (39%) of a white solid: mp 210°C.; ¹H NMR (DMSO-d₆): δ 6.89 (2H, d, J=8.58 Hz), 7.05 (1H, dd, J=2.42Hz, J=8.77 Hz), 7.17 (1H, d, J=2.24 Hz), 7.52 (1H, dd, J=1.68 Hz, J=8.40Hz), 7.61 (2H, d, J=8.58 Hz), 7.74 (1H, d, J=8.58 Hz), 7.79 (1H, d,J=8.58 Hz), 7.86 (1H, d, J=1.12 Hz), 9.60 (1H, bs), 9.72 (1H, bs); MS(ESI) m/z 235 (M−H)⁻.

[0153] Anal. for C₁₆H₁₂O₂: Calc'd:C: 81.34H: 5.12 Found: C: 81.23H: 5.09

EXAMPLE 1b 7-(3-Hydroxyphenyl)-2-naphthol

[0154] The title compound was prepared by reacting2-methoxy-7-(3-methoxyphenyl)naphthalene (0.52 g, 1.97 mmol) withpyridinium HCl (8 g) at 190° C. according to Method B to yield 0.13 g(28%) of a white solid: mp 163-165° C.; ¹H NMR (DMSO-d₆): δ 6.78-6.80(1H, m), 7.08 (1H, dd, J=2.56 Hz, J=8.54 Hz), 7.13-7.14 (1H, m),7.17-7.20 (2H, m), 7.27-7.30 (1H, m), 7.51 (1H, dd, J=2.14 Hz, J=8.54Hz), 7.70 (1H, d, J=8.97 Hz), 7.83 (1H, d, J=8.54 Hz), 7.90 (1H, d,J=1.28 Hz), 9.55 (1H, s), 9.78 (1H, s); MS (ESI) m/z235 (M−H)⁻.

[0155] Anal. for C₁₆H₁₂O₂: Calc'd:C: 81.34H:5.12 Found: C: 80.96H:5.07.

EXAMPLE 1c 7-Phenyl-2-naphthol

[0156] The title compound was prepared by reacting2-methoxy-7-phenylnaphthalene (0.53 g, 2.26 mmol) with pyridinium HCl(10 g) at 190° C. according to method B to yield 0.36 g (72%) of a whitesolid: mp 142-143° C.; ¹H NMR (DMSO-d₆): δ 7.10 (1H, dd, J=2.75 Hz,J=8.70 Hz), 7.23 (1H, d, J=2.29 Hz), 7.37-7.40 (1H, m), 7.48-7.51 (2H,m), 7.58 (1H, dd, J=1.83 Hz, 8.70 Hz), 7.78-7.90 (3H, m), 7.86 (1H, d,J=8.24 Hz), 7.99 (1H, d, J=0.92 Hz) 9.81 (1H, s); MS (ESI) m/z 219(M−H)⁻.

[0157] Anal. for C₁₆H₁₂O 0.1H₂O: Calc'd C:86.66H:5.47 Found:C:86.72H:5.62

[0158] Synthesis of Compounds in Scheme 2

Intermediate 6 6-(trifluoromethanesulfonate)-1-tetralone

[0159] In a 500 mL flask 6-hydroxy-1-tetralone (4.8 g, 29.6 mmol) wasazeotroped with xylenes and dissolved in anhydrous CH₂Cl₂ (220 mL). Thesolution was then cooled to 0° C. and anhydrous pyridine (3.35 mL, 41.4mmol) was added followed by triflic anhydride (10.0 g, 35.5 mmol). After0.5 h at 0° C. the reaction was quenched with sat. bicarbonate andwashed with water. The organic layer was passed through a silica plugand concentrated to 8.39 g (96%) product as a pale yellow oil: ¹H NMR(300 MHz, DMSO-d₆) δ 2.07 (2H, m), 2.65 (2H, t, J=6.5 Hz), 3.03 (2H, t,J=6.0 Hz), 7.47 (1H, dd, J=8.7 Hz, 2.3 Hz), 7.57 (1H, d, J=1.9 Hz), 8.03(1H, d, J=8.7 Hz).

Intermediate 7 6-(4-Hydroxyphenyl)-1-tetralone

[0160] 4-{[Tert-butyl(dimethyl)silyl]oxy}phenylboronic acid. In a 500 mLflask was added (4-bromophenoxy)-tert-butyldimethylsilane (15.0 g, 52.2mmol), and anhydrous THF (125 mL). The mixture was cooled to −78° C. andn-butyllithium (25 mL of 2.5 M solution in hexanes, 62.7 mmol) wasslowly added via syringe. After stirring for 0.5 h triisopropyl borate(60 mL, 261 mmol) was added and the solution was stirred for 1.5 h at−78° C. and then allowed to warm to ambient temperature. Then ice cold 2N HCl (150 mL) was added and the mixture was stirred for 10 minutes. Themixture was then extracted with ethyl acetate (3×), dried over Na₂SO₄,and concentrated to approximately 50 mL under reduced pressure. Hexaneswere added to the concentrate induced crystallization (3 crops) whichwas then collected by filtration and then dried under vacuum to give12.36 g (89%) of an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 0.19(6H, s), 0.95 (9H, s), 6.80 (2H, d, J=8.1 Hz), 7.67 (2H, d, J=8.1 Hz).

[0161] In a 500 mL flask was added6-(trifluoromethanesulfonate)-1-tetralone (5.0 g, 17.0 mmol),4-{[tert-butyl(dimethyl)silyl]oxy}phenylboronic acid (5.45 g, 20.4 mmol,prepared from above), sodium carbonate (4.56 g as 2 N aqueous, 42.5mmol), and tetrakis(triphenylphosphine)palladium(0) (0.98 g, 0.85 mmol)in DME (200 mL) was brought to reflux for 12 h. The reaction was allowedto cool, extracted with ethyl acetate (3×), and concentrated to a solid.The solids were washed with hexanes and dried under vacuum to 3.68 gproduct (92%) as a brown solid. mp 208-210° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 2.06 (2H, m), 2.60 (2H, t, J=6.5 Hz), 2.99 (2H, t, J=5.9 Hz),6.87 (2H, d, J=8.6 Hz), 7.57 (4H, m), 7.86 (1H, d, J=8.7 Hz), 9.74 (1H,s); MS m/z 237 (M−H⁺);

[0162] Anal. for C₁₆H₁₄O₂: Calc'd: C: 80.65H: 5.92 Found: C: 79.04H:5.60

EXAMPLE 1d 6-(4-Hydroxyphenyl)-1-naphthol

[0163] To a 25 mL flask was added 6-(4-hydroxyphenyl)-1-tetralone (500mg, 2.12 mmol), palladium on carbon (510 mg) and p-cymene (15 mL). Themixture was heated to reflux for 24 h, cooled, filtered through celiteand extracted with 1 M NaOH (2×25 mL). The aqueous layer was thenacidified, extracted with ether (3×), and passed through a silica plug.Concentration under reduced pressure afforded 260 mg (53%) product as abrown solid: mp above 200° C. (dec.); ¹H NMR (300 MHz, DMSO-d₆) δ 6.82(1H, d, J=7.5 Hz), 6.87 (2H, d, J=8.1 Hz), 7.29 (1H, t, J=7.5 Hz), 7.38(1H, d, J=7.5 Hz), 7.63 (2H, d, J=8.2 Hz), 7.70 (1H, d, J=8.5 Hz), 7.99(1H, s) 8.14 (1H, d, J=8.5 Hz), 9.59 (1H, s), 10.09 (1H, s); MS m/z 235(M−H^(+).)

[0164] Anal. for C₁₆H₁₂O₂: Calc'd: C: 81.34H: 5.12 Found: C: 81.22H:5.30

[0165] Synthesis of Compounds in Scheme 3

Intermediate 10 2-Methoxy-6-(4-methoxyphenyl)naphthalene

[0166] To a mixture of 2-bromo-6-methoxynaphthalene (23.79 g, 100.3mmol) and tetrakis(triphenylphosphine)palladium (5.8 g, 5 mmol) wasadded a solution of 4-methoxyphenylmagnesium bromide in THF (400 mL of0.5 N solution, 200 mmol). The stirred solution was heated to reflux for3 hr, cooled to RT, and stirred into 200 mL of 1 N HCl. The mixture wasextracted with dichloromethane and filtered through a short silica plugwith dichloromethane. The solvent was removed to yield a crude yellowsolid which was further purified by silica chromatography (20-50% ethylacetate-hexanes) to yield 25.68 g (97%) of the title compound as a whitesolid: mp 190° C.; ¹H NMR (CDCl₃): δ 3.86 (3H, s), 3.93 (3H, s), 7.01(2H, d, J=8.57 Hz), 7.14-7.18 (2H, m), 7.63 (2H, d, J=8.50 Hz), 7.67(1H, dd, J=1.68 Hz, J=8.73 Hz), 7.76-7.80 (2H, m), 7.91 (1H, d, J=0.94Hz); MS (ESI) m/z265 (M+H)⁺.

[0167] Anal. for C₁₈H₁₆O₂: Calc'd: C: 81.79H: 6.10 Found: C: 82.04H:6.17

Intermediate 11 2-(4-Methoxyphenyl)naphthalene

[0168] The title compound was prepared by reacting 2-bromonaphthalene(3.04 g, 14.7 mmol) with 4-methoxyphenylmagnesium bromide according tomethod used to prepared intermediate 10 to yield 2.89 g (89%) of a whitesolid: mp 114° C.; ¹H NMR (CDCl₃): δ 3.86 (3H, s), 7.01 (2H, d, J=9.06Hz), 7.43-7.50 (2H, m), 7.65 (2H, d, J=8.73 Hz), 7.71 (1H, dd, J=1.84Hz, J=8.56 Hz), 7.83-7.89 (3H, m), 7.98 (1H, d, J=0.67 Hz); MS (EI) m/z234 (M)⁺.

[0169] Anal. for C₁₇H₁₄O: Calc'd: C: 87.15H: 6.02 Found: C: 86.75H: 6.14

Intermediate 12 2-Methoxy-6-phenylnaphthalene

[0170] The title compound was prepared by reacting2-bromo-6-methoxynaphthalene (1.97 g, 8.31 mmol) with phenylmagnesiumbromide according to the method used to prepare intermedite 10 to yield1.59 g (82%) of a white solid: mp 122-126° C.; ¹H NMR (CDCl₃): δ 3.94(3H, s), 7.16-7.18 (2H, m), 7.34-7.37 (1H, m), 7.46-7.49 (2H, m),7.69-7.72 (2H, m), 7.78-7.82 (2H, m), 7.97 (1H, s); MS (EI) m/z 234.2(M)⁺.

[0171] Anal. for C₁₇H₁₄O: Calc'd: C: 87.15H: 6.02 Found: C: 86.79H: 6.14

Intermediate 13 2-Methoxy-6-(3-methoxyphenyl)naphthalene

[0172] The title compound was prepared by reacting6-methoxy-2-bromonaphthalene (3.09 g, 13.0 mmol) with3-methoxyphenylboronic acid (2.18 g, 14.3 mmol according to method A toyield 1.18 g (34%) of a white solid: mp 80° C.; ¹H NMR (CDCl₃): δ 3.88(3H, s), 3.92(3H, s), 6.90 (1H, dd, J=2.17 Hz, J=7.76 Hz), 7.14-7.18(2H, m), 7.22-7.24 (1H, m), 7.28 (1H, d, J=7.45 Hz), 7.36-7.39, (1H, m),7.70 (1H, dd, J=1.86 Hz, J=8.70 Hz), 7.77-7.80 (2H, m), 7.96 (1H, d,J=1.24 Hz); MS (ESI) m/z 265 (M+H)⁺.

[0173] Anal. for C₁₈H₁₆O₂: Calc'd: C: 81.79H: 6.10 Found: C: 81.61H:6.47

EXAMPLE 1i 6-(3-Chlorophenyl)-2-naphthol

[0174] A mixture of 6-bromo-2-naphthol (1.78 g, 8.0 mmol),2-chlorophenylboronic acid (1.5 g, 9.6 mmol), sodium carbonate (2.11 gas 2 N aqueous, 20.0 mmol), and tetrakis(triphenylphosphine)palladium(0)(550 mg, 0.48 mmol) in DME (95 mL) was were reacted according to MethodA. Column chromatography (30% ethyl acetate-hexanes) produced 520 mg(26%) of product as a tan solid: mp 116-118° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 7.13 (2H, m), 7.42 (1H, td, J=7.9 Hz, 0.9 Hz), 7.51 (1H, t,J=7.6 Hz), 7.80 (5H, m), 8.16 (1H, s), 9.88 (1H, s); MS m/z253/255 (Clpattern) (M−H⁺);

[0175] Anal. for C₁₆H₁₁CIO: Calc'd: C: 75.45H: 4.35 Found: C: 75.20H:4.34

EXAMPLE 1e 6-(4-Hydroxyphenyl)-2-naphthol

[0176] 2-Methoxy-6-(4-methoxyphenyl)naphthalene (5.61 g, 21.2 mmol) wasadded to pyridinium HCl (30 g) at 190° C. according to Method B toafford 4.88 g (98%) of a white solid: mp>220 (discolors above 200° C.);¹H NMR (DMSO-d₆): δ 6.87 (2H, d, J=8.54 Hz), 7.08 (1H, dd, J=2.34 Hz,J=8.76 Hz), 7.11 (1H, d, J=2.14 Hz), 7.58 (2H, d, J=8.54 Hz), 7.65 (1H,dd, J=1.92 Hz, J=8.76 Hz), 7.71 (1H, d, J=8.54 Hz), 7.79 (1H, d, J=8.97Hz), 7.95 (1H, s), 9.56 (1H, bs), 9.70 (1H, bs); MS (ESI) m/z 235(M−H)⁻.

[0177] Anal. for C₁₆H₁₂O₂: Calc'd: C: 81.34H: 5.12 Found: C: 81.05H:5.18

EXAMPLE 1f 4-(2-Naphthyl)phenol

[0178] The title compound was prepared by reacting2-(4-methoxyphenyl)naphthalene (1.01 g, 4.31 mmol) with 10 g ofpyridinium HCl at 190° C. according to method B to yield 0.84 g (89%) ofa white solid: mp 148° C.; ¹H NMR (DMSO-d₆): δ 6.92 (2H, d, J=8.71 Hz),7.46-7.53 (2H, m), 7.66 (2H, d, J=8.71 Hz), 7.79 (1H, dd, J=1.78 Hz,J=8.51 Hz), 7.90 (1H, d, J=8.31 Hz), 7.95 (2H, d, J=8.31 Hz), 8.11 (1H,d, J=1.19 Hz), 9.65 (1H, s); MS (ESI) m/z 219 (M−H)⁻.

[0179] Anal. for C₁₆H₁₂O₂: Calc'd: C: 87.25H: 5.49 Found: C: 87.31H:5.86

EXAMPLE 1g 6-Phenyl-2-naphthol

[0180] The title compound was prepared by reacting2-methoxy-6-phenylnaphthalene (0.54 g, 2.30 mmol) with of pyridinium HCl(10 g) at 190° C. according to method B to yield 0.32 g (63%) of a lightpink solid: mp 169-170° C.; ¹H NMR (DMSO-d₆): δ 7.12 (1H, dd, J=2.56 Hz,J=8.54 Hz), 7.16 (1H, d, J=2.56 Hz), 7.35-7.38 (1H, m), 7.47-7.50 (2H,m), 7.73 (1H, dd, J=1.71 Hz, J=8.54 Hz), 7.76-7.79 (3H, m), 7.85 (1H, d,J=8.54 Hz), 8.08 (1H, d, J=1.28 Hz), 9.82 (1H, s); MS (ESI) m/z 219(M−H)⁻.

[0181] Anal. for C₁₆H₁₂O: Calc'd: C: 87.25H:5.49 Found: C: 87.05H:5.55

EXAMPLE 1 h 6-(3-Hydroxyphenyl)-2-naphthol

[0182] The title compound was prepared by reacting2-methoxy-6-(3-methoxyphenyl)naphthalene (0.51 g, 1.90 mmol) withpyridinium HCl (6 g) at 190° C. according to method B to yield 0.21 g(47%) of an off white solid: mp 192-194° C.; ¹H NMR (DMSO-d₆): δ6.75-6.78 (1H, m), 7.10-7.14 (3H, m), 7.16-7.18 (1H, m), 7.65 (1H, dd,J=1.79 Hz, J=8.57 Hz), 7.75 (1H, d, J=8.77 Hz), 7.84 (1H, d, J=8.77 Hz),8.01 (1H, d, J=1.59 Hz), 9.51 (1H, s), 9.78, (1H, s); MS (ESI) m/z 235(M−H)⁻. Anal. for C₁₆H₁₂O₂:

[0183] Calc'd: C: 81.34H: 5.12 Found: C: 80.94H: 5.09

[0184] Synthesis of Compounds in Scheme 4

Intermediate 14 1-Bromo-2-methoxy-6-(4-methoxyphenyl)naphthalene

[0185] To a mixture of 2-methoxy-6-(4-methoxyphenyl)naphthalene (9.68 g,36.6 mmol) and glacial acetic acid (150 mL) was slowly added a solutionof bromine (5.85 g, 36.6 mmol) in glacial acetic acid (20 mL). Themixture was stirred for 1 hour and the resulting suspension was pouredinto water (200 mL) and the solid product was collected by filtration.The solid was triturated first with water and then with ethyl acetate toyield 11.25 g (90%) of the title compound as a white solid: mp 172-174°C.; ¹H NMR (CDCl₃): δ 3.88 (3H, s), 4.05 (3H, s), 7.04 (2H, d, J=8.56Hz), 7.30 (1H, d, J=9.01 Hz), 7.67 (2H, d, J=8.65 Hz), 7.81 (1H, dd,J=1.61 Hz, J=8.84 Hz), 7.87 (1H, d, J=9.04 Hz), 7.94 (1H, d, J=1.47 Hz),8.27 (1H, d, J=8.92 Hz); MS (EI) m/z 343 (M)⁺.

[0186] Anal. for C₁₈H₁₅BrO₂: Calc'd: C: 62.99H: 4.41 Found: C: 62.66H:4.57

Intermediate 15 1-Chloro-2-methoxy-6-(4-methoxyphenyl)naphthalene

[0187] Method C

[0188] A suspension of 2-methoxy-6-(4-methoxyphenyl)naphthalene (0.51 g,1.93 mmol) and NCS (0.28 g, 2.13 mmol) in acetonitrile (20 mL) washeated to reflux for 3 hr. The resulting solution was cooled to roomtemperature and the resulting solid was collected by filtration andrinsed with acetonitrile to yield 0.41 g (72%) of the title compound asa white solid: mp 158-164° C.; ¹H NMR (CDCl₃): δ 3.87 (3H, s), 4.05 (3H,s), 7.03 (2H, d, J=8.62 Hz), 7.32 (1H, d, J=9.02 Hz), 7.65 (2H, d,J=8.55 Hz), 7.82 (2H, d, J=9.01 Hz), 7.95 (1H, d, J=1.36 Hz), 8.27 (1H,d, J=8.81 Hz); MS (EI) m/z 298 (M)⁺.

[0189] Anal. for C₁₈H₁₅ClO₂: Calc'd: C: 72.36H: 5.06 Found: C: 72.06H:4.89

EXAMPLE 1o 1-Bromo-6-(4-hydroxyphenyl)-2-naphthol

[0190] To a solution of 6-(4-hydroxyphenyl)-2-naphthol (4.02 g, 17.0mmol) in acetonitrile (150 mL) at 0° C. was added NBS (3.03 g, 17.0mmol). The reaction was stirred at 0° C. for 3 hr and then poured intowater (200 mL) and extracted with ethyl acetate (3×300 mL). The combinedorganic layers were washed with water, dried over sodium sulfate,filtered, evaporation of the solvent, and purification by silica columnchromatography (20% ethyl acetate—hexanes) yielded 5.33 g (100%) of thetitle compound as a tan solid. The title compound was further purifiedby reverse phase HPLC to yield a white solid: mp 208-210° C.; ¹H NMR(DMSO-d₆): δ 6.89 (2H, d, J=8.47 Hz), 7.28 (1H, d, J=8.80 Hz), 7.63 (2H,d, J=8.50 Hz), 7.85 (2H, d, J=8.84 Hz), 8.02-8.06 (2H, m), 9.60 (1H, s),10.54 (1H, s); MS (ESI) m/z 313/315 (M−H)⁻.

[0191] Anal. for C₁₆H₁₁BrO₂: Calc'd: C: 60.98H: 3.52 Found: C: 60.63H:3.46

EXAMPLE 1p 1-Chloro-6-(4-hydroxyphenyl)-2-naphthol

[0192] The title compound was prepared by reacting1-chloro-2-methoxy-6-(4-methoxyphenyl)naphthalene (0.32 g, 1.07 mmol)with pyridinium HCl (7 g) at 190° C. according to method B to yield 0.12g (41%) of an off white solid: mp 222-224° C. (dec.);

[0193]¹H NMR (DMSO-d₆): δ 6.88 (2H, d, J=8.46 Hz), 7.29 (1H, d, J=8.88Hz), 7.63 (2H, d, J=8.50 Hz), 7.81-7.88 (2H, m), 8.02-8.08 (2H, m), 9.59(1H, s), 10.43(1H, s); MS (ESI) m/z 269/271 (M−H)⁻.

[0194] Anal. for C₁₆H₁₁ClO₂:: Calc'd: C: 70.99H:4.10 Found: C:70.59H:4.12

EXAMPLE 1q 6-(4-Hydroxyphenyl)-1-methoxy-2-naphthol

[0195] A mixture of 1-bromo-6-(4-hydroxyphenyl)-2-naphthol (0.41 g, 1.30mmoles), CuBr (0.19 g, 0.13 mmoles), sodium methoxide (3 ml of 4.4 N inmethanol), and DMF (6 ml) was heated to reflux for 3 hours. The reactionmixture was cooled to room temperature, poured into HCl (50 ml of 1 Naqueous solution), and extracted with ethyl acetate (3×100 ml). Thecombined organic layers were washed with sodium bicarbonate solution,dried over sodium sulfate, filtered, stripped of solvent, and purifiedby silica column chromatgraphy (40% ethyl acetate—hexanes) to yield 0.31g (89%) of the title compound as a white solid: mp 204-206° C.; ¹H NMR(DMSO-d₆): δ 6.88 (2H, d, J=8.47 Hz), 7.19 (1H, d, J=8.81 Hz), 7.57-7.60(3H, m), 7.71 (1H, dd, J=1.41 Hz, J=8.78 Hz), 7.94-7.98 (2H, m), 9.54(2H, s); MS m/z (M−H)— =265;

[0196] Anal. for C₁₇H₁₄O₃: Calc'd: C:76.68H:5.30 Found: C:76.46H:5.13

[0197] Synthesis of Compounds in Scheme 5

Intermediate 16 2-Methoxy-6-(4-methoxyphenyl)-1-fluoronaphthalene

[0198] To a solution of 2-methoxy-6-(4-methoxyphenyl)-1-bromonaphthalene(1.28 g, 3.72 mmol) in THF (25 mL) at −78° C. was slowly added n-butyllithium (1.9 mL of 2.5 N in hexanes). The resulting solution was stirredat −78° C. for thirty minutes and a solution ofN-fluorobenzenesulfonimide (1.40 g, 4.5 mmol) in THF (10 mL) was added.After 2 additional hr at −78° C., the reaction was warmed to roomtemperature, poured in water, and extracted with ethyl acetate (2×250mL). The combined organic layers were washed with water, dried oversodium sulfate, filtered, evaporation of the solvent, and purificationby silica chromatography (5% THF—hexanes) yielded 0.66 g (63%) of awhite solid: mp 150-155° C.; ¹H NMR (CDCl₃): δ 3.88 (3H, s), 4.04 (3H,s), 7.02 (2H, d, J=8.69 Hz), 7.28-7.34 (1H, m), 7.62-7.67 (3H, m), 7.74(1H, dd, J=1.60 Hz, J=8.79 Hz), 7.93 (1H, s), 8.09 (1H, d, J=8.77 Hz).

[0199] Anal. for C₁₈H₁₅O₂F: Calc'd: C: 76.58H: 5.36 Found: C: 75.78H:5.95

Intermediate 17 2-Methoxy-6-(4-methoxyphenyl)-1-napthonitrile

[0200] A mixture of 1-bromo-2-methoxy-6-(4-methoxyphenyl)naphthalene(0.76 g, 2.21 g), CuCN (0.24 g, 2.66 mmol) and DMF (10 mL) was stirredat 120° C. for 4 hr. The reaction mixture was cooled to roomtemperature, slurried with ethyl acetate, filtered through silica, andevaporation of the solvent, and purification by silica columnchromatography (20% ethyl acetate—hexanes) yielded 0.19 g (30%) of thetitle compound as a pale yellow solid: mp 182-185° C.; ¹H NMR (CDCl₃): δ3.88 (3H, s), 4.09 (3H, s), 7.03 (2H, d, J=8.73 Hz), 7.29 (1H, d, J=9.12Hz), 7.63 (2H, d, J=8.73 Hz), 7.88 (1H, dd, J=1.98 Hz, J=8.73 Hz), 7.97(1H, d, J=1.98 Hz), 8.09 (1H, d, J=9.12 Hz), 8.14 (1H, d, J=8.73 Hz).

[0201] Anal. for C₁₉H₁₅O₂N: Calc'd: C: 78.87H: 5.23 N: 4.84 Found: C:79.06H: 7.27 N: 2.91

Intermediate 18 2-Methoxy-6-(4-methoxyphenyl)-1-phenylnaphthalene

[0202] To a mixture of 2-methoxy-6-(4-methoxyphenyl)-1-bromonaphthalene(0.80 g, 2.33 mmol) and tetrakis(triphenylphosphine)palladium (0.13 g,0.12 mmol) in THF (10 mL) was added phenylmagnesiumbromide (2.2 mL of 3N in ether). The reaction mixture was stirred at reflux overnight,cooled to room temperature, poured into 1 N HCl (100 mL), and extractedwith ethyl acetate (3×200 mL). The combined organic layers were washedwith sodium bicarbonate solution, dried over magnesium sulfate,filtered, evaportation of the solvent, and purification by silica columnchromatography (10% ethyl acetate-hexanes) yielded 0.42 g (53%) of agray solid: mp 157-160° C.; ¹H NMR (CDCl₃): δ 3.85 (3H, s), 3.87 (3H,s), 7.01 (2H, d, J=8.64 Hz), 7.38-7.46 (4H, m), 7.49-7.57 (4H, m), 7.64(2H, d, J=8.64 Hz), 7.92 (1H, d, J=9.05 Hz), 7.97 (1H, s); MS (ESI) m/z341 (M+H)⁺.

[0203] Anal. for C₂₄H₂₀O₂ 0.5H₂O: Calc'd: C: 82.50H: 6.06 Found: C:82.60H: 5.66

Intermediate 19 2-Methoxy-6-(4-methoxyphenyl)-1-methylnaphthalene

[0204] To a solution of 2-methoxy-6-(4-methoxyphenyl)-1-bromonaphthalenein THF (25 mL) at 0° C. was slowly added n-butyl lithium (2 mL of 2.5N)and TMEDA (0.60 g, 5.13 mmol, freshly distilled from KOH). After thirtyminutes at 0° C. iodomethane (7.3 g, 51.3 mmol, passed through basicalumina) was added and the stirring solution was allowed to warm to roomtemperature overnight. The reaction was poured into water (100 mL) andextracted with ethyl acetate (3×200 mL). The combined organic layerswere washed with water, dried over magnesium sulfate, filtered,evaporation of the solvent, and purification by silica columnchromatography (5% THF-hexanes) yielded 0.63 g (88%) of a white solid:mp 136-138° C.; ¹H NMR (CDCl₃): δ 3.87 (3H, s), 3.96 (3H, s), 7.02 (2H,d, J=8.74 Hz), 7.29 (1H, d, J=9.01 Hz), 7.60-7.80 (4H, m), 7.95 (1H, d,J=1.76 Hz), 8.00 (1H, d, J=8.86 Hz); MS (ESI) m/z279 (M+H)⁺.

[0205] Anal. for C₁₉H₁₈0₂ 0.3H₂O: Calc'd: C: 80.43H: 6.61 Found: C:80.20H: 6.33

EXAMPLE 1r 1-Fluoro-6-(4-hydroxyphenyl)-2-naphthol

[0206] The title compound was prepared by reacting2-methoxy-6-(4-methoxyphenyl)-1-fluoronaphthalene (0.250 g, 0.886 mmol)with boron tribromide (2.7 mL of 1 N solution, 2.7 mmol) according tomethod D to yield 0.13 g (15%) of a white solid: mp 219-224° C.;

[0207]¹H NMR (DMSO-d₆): δ 6.89 (2H, d, J=8.49 Hz), 7.22-7.28 (1H, m),7.61 (2H, d, J=8.53 Hz), 7.65 (1H, d, J=9.12 Hz), 7.79 (1H, d, J=8.77Hz), 7.92 (1H, d, J=8.73 Hz), 8.05 (1H, s), 9.63 (1H, bs), 10.00 (1H,bs); MS (ESI) m/z 253 (M−H)⁻.

[0208] Anal. for C₁₆H₁₁FO₂:: Calc'd: C: 75.58H: 4.36 Found: C: 75.13H:4.40

EXAMPLE 1s 2-Hydroxy-6-(4-hydroxyphenyl)-1-naphthonitrile

[0209] The title compound was prepared by reacting2-methoxy-6-(4-methoxyphenyl)-1-napthonitrile (0.115 g, 0.397 mmol) withpyridinium HCl (4 g) at 190° C. according to method D to yield 0.025 g(24%) of a tan solid: mp>220° C.; ¹H NMR (DMSO-d₆): δ 6.89 (2H, d,J=8.37 Hz), 7.28 (1H, d, J=9.07 Hz), 7.63 (2H, d, J=8.42 Hz), 7.88-7.98(2H, m), 8.12-8.16 (2H, m), 9.63 (1H, s), 11.65 (1H, bs); MS (ESI)m/z260 (M−H)⁻

[0210] Anal. for C₁₇H₁₁NO₂ 0.4H₂O: Calc'd: C: 76.05H: 4.43 N: 5.22Found: C: 76.09H: 4.25 N: 4.83.

EXAMPLE 1t 6-(4-Hydroxyphenyl)-1-phenyl-2-naphthol

[0211] Method D

[0212] To a mixture of 2-methoxy-6-(4-methoxyphenyl)-1-phenylnaphthalene(0.36 g, 1.06 mmol) in CH₂Cl₂ (25 mL) at 0° C. was slowly added borontribromide (3.2 mL of 1 N in CH₂Cl₂). The mixture was allowed to warmslowly to room temperature and was stirred overnight. The resultingsolution was poured into water (100 mL) and extracted with ethyl acetate(3×150 mL). The combined organic layers were washed with saturatedsodium bicarbonate solution, dried over magnesium sulfate, evaporationof thesolvent, and purification by silica column chromatography (25%ethyl acetate-hexanes) followed by preparative reverse-phase HPLC anddrying under vacuum at 105° C. yielded 0.14 g (42%) of the titlecompound as a white solid: mp 142-146° C.; ¹H NMR (DMSO-d₆): δ 6.86 (2H,d, J=8.50 Hz), 7.26-7.42 (5H, m), 7.48-7.61 (5H, m), 7.84 (1H, d, J=8.96Hz), 8.02 (1H, d, J=1.46 Hz), 9.52 (2H, s); MS (ESI) m/z 311 (M−H)⁻.

[0213] Anal. for C₂₂H₁₆O₂ 0.1H₂O: Calc'd: C: 84.11H: 5.20 Found: C:83.90H: 5.15

EXAMPLE 1u 6-(4-Hydroxyphenyl)-1-methyl-2-naphthol

[0214] The title compound was prepared by reacting2-methoxy-6-(4-methoxyphenyl)-1-methylnaphthalene (0.35 g, 1.26 mmol)with boron tribromide 3.8 mL of 1 N solution, 3.8 mmol) according tomethod D to yield 0.15 g (48%) of a white solid: mp>170° C. (dec.); ¹HNMR (DMSO-d₆): δ 2.42 (3H, s), 6.87 (2H,k d, J=8.33 Hz), 7.15 (1H, d,J=8.81 Hz), 7.59 (2H, d, J=8.35 Hz), 7.65 (1H, d, J=8.93 Hz), 7.71 (1H,dd, J=1.24 Hz, J=8.90 Hz), 7.88 (1H, d, J=8.87 Hz), 7.95 (1H, s), 9.49(1H, s), 9.52 (1H, s); MS (ESI) 249 m/z(M−H)⁻.

[0215] Anal. for C₁₇H₁₄O₂: Calc'd: C:81.58H:5.64 Found: C:81.15H:5.58

[0216] Synthesis of Compounds in Scheme 6

Intermediate 27 Tert-butyl[(6-bromo-2-naphthyl)oxy]dimethylsilane

[0217] Method E

[0218] To a solution of 6-bromo-2-naphthol (13.68 g, 61.33 mmol) andTBDMS-CI (11.09 g, 73.6 mmol) in DMF (50 mL) was added imidazole (10.2g, 150 mmol). The solution was stirred for 3 hr, mixed with sodiumbicarbonate solution (250 mL), and extracted with 50% ethylacetate-hexanes (3×250 mL). The combined organic layers were washed withwater, dried over magnesium sulfate, filtered and evaporation of thesolvent yielded a tan oil which was dried under vacuum to yield 19.92 g(97%) of the title compound as a white solid:

[0219]¹H NMR (CDCl₃): δ 0.24 (6H, s), 1.01 (9H, s), 7.08 (1H, dd, J=2.26Hz, J=8.81 Hz), 7.14 (1H, d, J=2.15 Hz), 7.46 (1H, dd, J=1.80 Hz, J=8.77Hz), 7.54 (1H, d, J=8.77 Hz), 7.61 (1H, d, J=8.81 Hz), 7.90 (1H, s); MS(EI) m/z336/338 (M)⁺.

[0220] Anal. for C₁₆H₂₁BrO₁Si 0.25H₂O: Calc'd: C: 56.97H: 6.27 Found: C:56.81H: 6.43

Intermediate 22 Tert-butyl(4-bromo-2,6-difluoro-phenyloxy)dimethylsilane

[0221] The title compound was prepared by reacting4-bromo-2,6-difluoro-phenol (10.54 g, 50.4 mmol) with TBDMS-CI (9.88 g,150.7 mmol) according to method E to yield 14.61 g (90%) of a clear,colorless, oil: ¹H NMR (CDCl₃) δ 0.17 (6H, s), 0.99 (9H, s),7.02(H,d,J=7.13 Hz). INTERMEDIATE 28

[0222] Tert-butyl[(2-(6-naphthyl boronic acid)oxy]dimethylsilane MethodF To a solution of tert-butyl[(6-bromo-2-naphthyl)oxy]dimethylsilane(19.18 g, 56.9 mmol) in THF (200 mL) at −78° C. was slowly added n-butyllithium (25 mL of 2.5 N solution in hexanes). The solution was stirredfor thirty minutes and triisopropyl borate (53.5 g, 285 mmol) was added.The solution was stirred for 1 hour at −78° C. and then allowed to warmto room temperature overnight. The solution was then cooled to 0° C. andstirred with HCl (200 mL of 1 N solution) for 10 minutes. The mixturewas extracted with ethyl acetate (3×250 mL). The combined organic layerswere concentrated to a volume of 25 mL. Crystallization was induced withhexanes, and the solid product was collected by filtration and driedunder vacuum to yield 13.5 g (79%) of the title compound as an off whitesolid:

[0223]¹H NMR (DMSO-d₆): δ 0.25 (6H, s), 0.99 (9H, s), 7.10 (1H, dd,J=2.56 Hz, J=8.97 Hz), 7.26 (1H, d, J=2.56 Hz), 7.73 (1H, d, J=8.54 Hz),7.82 (1H, dd, J=1.07 Hz, J=8.33 Hz), 7.83 (1H, d, J=8.97 Hz), 8.30 (1H,s); MS (ESI) m/z 303 (M+H)⁺.

[0224] Anal. for C₁₆H₂₃BO₃Si: Calc'd: C: 63.58H: 7.67 Found: C: 46.97H:6.78

Intermediate 29 3-Fluoro-4-methoxyphenylboronic Acid

[0225] The title compound was prepared by reacting4-bromo-2-fluoroanisole (10 g, 0.049 mol) with n-butyl lithium (23.4 mLof 2.5 M solution in hexane, 0.059 mol) followed by triisopropyl borate(45.2 mL, 36.9 g, 0.196 mol) according to method F to yield 7.1 g(85.2%) of a white solid-MS (ESI) m/z 169 (M−H)⁻: ¹H NMR (DMSO-d₆): δ3.84 (3H, s), 7.10-7.16 (1H, m), 7.51-7.60 (2H, m).

Intermediate 30 3,5-Difluoro-4-tert-butyldimethylsilyoxyboronic Acid

[0226] The title compound was prepared by reactingtert-butyl(4-bromo-2,6-difluorophenyloxy)dimethylsilane (12.98 g, 40.19mmol) with n-butyl lithium (27.6 mL of 1.6N solution, 44.2 mmol)followed by triisopropyl borate (37.8 g, 200 mmol) according to method Fto yield 4.38 g (38%) of a white solid: ¹H NMR (DMSO-d₆): δ 0.25 (6H,s), 1.06 (9H, s), 7.54 (2H, d, J=7.93 Hz).

Intermediate 31 4-Methoxy-2-methylphenylboronic Acid

[0227] The title compound was prepared by reacting4-bromo-3-methylanisole (10 g, 0.050 mol) with n-butyl lithium (24 mL of2.5 M solution in hexane, 0.055 mol) followed by triisopropyl borate(57.7 mL, 47.02 g, 0.25 mol) according to method F to yield 5.7 g (69%)of a white solid: MS (ESI) m/z 313 (2M−H₂O—H)⁻.

Intermediate 33 2-(3-Fluoro-4-methoxyphenyl)naphthalene

[0228] The title compound was prepared by reacting 2-bromonaphthalene(0.31 g, 1.50 mmol) with 3-fluoro-4-methoxyphenylboronic acid (0.31 g,1.80 mmol) according to method A to yield 0.30 g (79%) of a white solid:mp 108-110° C.; ¹H NMR (CDCl₃): δ (3.96, 3H, s), 7.04-7.10 (1H, m),7.43-7.52 (4H, m), 7.68 (1H, dd, J=1.81 Hz, J=8.57 Hz), 7.84-7.92 (3H,m), 7.97 (1H, d, J=1.05 Hz).

[0229] Anal. for C₁₇H₁₃FO:: Calc'd: C: 80.93H: 5.19 Found: C: 81.01H:4.78

EXAMPLE 1ay 6-(3,5-Difluoro-4-hydroxyphenyl)-2-naphthol

[0230] The title compound was prepared by reacting 6-bromo-2-naphthol(0.165 g, 0.74 mmol) with3,5-difluoro-4-tert-butyldimethylsilyoxyboronic acid (0.25 g, 0.87 mmol)according to method A to yield 0.14 g (70%) of a tan solid. Thismaterial was further purified by preparative reverse phase HPLC to yieldthe title compound as a white solid: mp 216-220° C.; ¹H NMR (DMSO-d₆): δ7.09-7.13 (2 h, m), 7.50 (2H, d, J=10.00 Hz), 7.73 (2H, s), 7.78 (1H, d,J=8.58 Hz), 8.10 (1H, s), 9.83 (1H, s), 10.28H, s); MS (ESI) m/z271(M−H)⁻.

[0231] Anal. for C₁₆H₁₀F₂O₂ 0.25H₂O: Calc'd: C: 69.44H: 3.82 Found: C:69.70H: 3.63

Intermediate 34 6-(3-Fluoro-4-methoxyphenyl)-2-naphthol

[0232] The title compound was prepared by reacting 6-bromo-2-naphthol(3.2 g, 18.8 mmol) with 3-fluoro-4-methoxyphenylboronic acid (3.5 g,15.7 mmol) according to method A to yield 3.3 g (78%) of white solid: mp174-176° C.; ¹H NMR (DMDO-d₆): δ 3.89 (3H, s), 7.11 (1H, dd, J=8.79 Hz,J=1.95 Hz), 7.13 (1H, s), 7.26 (1H, J=8.79 Hz), 7.57 (1H, d, J=8.79 Hz),7.66 (1H, dd, J=13.18 Hz, J=1.95 Hz), 7.71 (1H, dd, J=8.79 Hz, J=1.46Hz), 7.75 (1H, d, J=8.79 Hz), 7.82 (1H, d, J=8.79 Hz), 8.07 (1H, s),9.81 (1H, s); MS (ESI) m/z267 (M−H)⁻.

[0233] Anal. for C₁₇H₁₃FO₂: Calc'd: C: 76.11H: 4.88 Found: C: 76.03H:4.78

Intermediate 35 6-(4-Methoxy-2-methylphenyl)-2-naphthol

[0234] The title compound was prepared by reacting 6-bromo-2-naphthol(1.8 g, 5.4 mmol) with 4-methoxy-3-methylphenylboronic acid (1.74 g, 7.0mmol) according to method A to yield 1.56 g (73%) of yellowish solid: mp124-126° C.; ¹H NMR (DMDO-d₆): δ 2.25(3H,s), 3.78 (3H, s), 6.85 (1H, dd,J=8.35 Hz, J=2.56 Hz), 6.90 (1H, d, J=2.37 Hz), 7.09 (1H, dd, J=8.75 Hz,J=2.25 Hz), 7.13 (1H, s), 7.20 (1H, d, J=8.33 Hz), 7.35 (1H, dd, J=8.39Hz, J=1.37 Hz), 7.67 (1H,s), 7.70 (1H, d, J=8.53 Hz), 7.78 (1H, d,J=8.78 Hz), 9.74 (1H, s); MS (ESI) m/z263 (M−H)⁻.

[0235] Anal. for C₁₈H₁₆O₂: Calc'd: C: 81.79H: 6.10 Found: C: 81.43H:6.01

EXAMPLE 1j 2-Fluoro-4-(2-naphthyl)phenol

[0236] The title compound was prepared by reacting2-(3-fluoro-4-methoxyphenyl)naphthalene (0.22 g, 0.87 mmol) with borontribromide (1.75 mL of 1 N solution, 1.75 mmol) according to method D toyield 0.13 g (63%) of a white solid: mp 110-112° C.; ¹H NMR (DMSO-d₆): δ7.05-7.11 (1H, m), 7.47-7.54 (3H, m), 7.65 (1H, dd, J=2.20 Hz, J=12.92Hz), 7.82 (1H, dd, J=1.80 Hz, J=8.62), 7.90-7.98 (3H, m), 8.17 (1H, bs),10.07 (1H, bs); MS (ESI) m/z237 (M−H)⁻.

[0237] Anal. for C₁₆H₁₁FO: Calc'd: C: 80.66H: 4.65 Found: C: 80.31H:4.29

EXAMPLE 1k 6-(3-Fluoro-4-hydroxyphenyl)-2-naphthol

[0238] The title compound was prepared by reacting6-(3-fluoro-4-methoxyphenyl)-2-naphthol (600 mg, 2.24 mmol) with borontribromide (6.27 mL of 1.0 M solution in CH₂Cl₂, 6.27 mmol) according tomethod D to yield 385 mg (68%) of a yellowish solid: mp 216-219° C.; ¹HNMR (DMDO-d₆): δ 7.03-7.13 (3H, m), 7.43 (1H, dd, J=8.37 Hz, J=1.77 Hz),7.58 (1H, dd, J=12.92 Hz, J=2.13 Hz), 7.68 (1H, dd, J=8.68 Hz, J=1.61Hz), 7.74 (1H, d, J=8.68 Hz), 8.03 (1H, s), 9.79 (1H, s), 9.98 (1H, s);MS (ESI) m/z 253 (M−H)⁻. Anal. for C₁₆H₁₁FO₂.0.13H₂O:

[0239] Calc'd: C:74.89H:4.42 Found: C:74.86H:4.33

[0240] Synthesis of Compounds in Scheme 7

Intermediate 36 1-Chloro-6-(3-fluoro-4-methoxyphenyl)-2-naphthol

[0241] The title compound was prepared by reacting6-(3-fluoro-4-methoxylphenyl)-2-naphthol (1 g, 3.73 mmol) and NCS (748mg, 5.60 mmol) in THF (35 mL) according to method A to yield 780 mg(69%) of brown solid: mp 137-139° C.; ¹H NMR (DMDO-d₆): δ 3.89 (3H, s),7.26-7.33 (2H, m), 7.61 (1H, d, J=8.63 Hz), 7.71 (1H, dd, J=13.08 Hz,J=2.16 Hz), 7.84 (1H, d, J=8.93 Hz), 7.92 (1H, dd, J=8.92 Hz, J=1.80Hz), 8.06 (1H, d, J=8.86 Hz), 8.19 (1H, d, J=1.55 Hz), 10.52 (1H, s); MS(ESI) m/z301/303(M−H)⁻.

[0242] Anal. for C₁₆H₁₁ClO: Calc'd: C: 67.45H: 4.00 Found: C: 67.35H:3.78

Intermediate 37 1-Chloro-6-(4-methoxy-2-methylphenyl)-2-naphthol

[0243] The title compound was prepared by reacting6-(4-methoxy-2-methylphenyl)-2-naphthol (800 mg, 3.03 mmol) and NCS (485mg, 3.61 mmol) in THF (30 mL) according to method A to yield 640 mg(71%) of yellow solid: ¹H NMR (DMDO-d₆): δ 2.26 (3H, s), 3.79 (3H, s),6.86 (1H, dd, J=8.36 Hz, J=2.63 Hz), 6.91 (1H, d, J=2.51 Hz), 7.22 (1H,d, J=8.34 Hz), 7.31 (1H, d, J=8.89 Hz), 7.56 (1H, dd, J=8.71 Hz, J=1.71Hz), 7.79-7.83(2H, m), 8.04 (1H, J=8.91 Hz), 10.46 (1H, s); ¹³C NMR(DMDO-d₆): δ 20.54, 55.07, 111.48, 112.21, 115.71, 118.73, 121.94,127.92, 128.15, 128.35, 129.34, 130.12. 130.87, 133.26, 136.14, 136.36,150.99, 158.49; MS (ESI) m/z297/299 (M−H)⁻.

[0244] Anal. for C₁₈H₁₅ClO₂: Calc'd: C: 72.36H: 5.06 Found: C: 72.02H:5.03

EXAMPLE 1v 1-Chloro-6-(3-fluoro-4-hydroxyphenyl)-2-naphthol

[0245] The title compound was prepared by reacting1-chloro-6-(3-fluoro-4-methoxyphenyl)-2-naphthol (420 mg, 1.39 mmol)with boron tribromide (3.9 mL of 1.0 M solution in CH₂Cl₂, 3.89 mmol)according to method D to yield 330 mg (82%) of a yellowish solid: mp195-198° C.; ¹H NMR (DMDO-d₆): δ 7.08 (1H, t, J=8.86 Hz), 7.32 (1H, d,J=8.89 Hz), 7.47 (1H, dd, J=8.42 Hz, J=1.52 Hz), 7.63 (1H, dd, J=12.88Hz, J=1.98 Hz), 7.83 (1H, d, J=8.95 Hz), 7.88 (1H, dd, J=8.93 Hz, J=1.61Hz), 8.05 (1H, d, 8.86 Hz), 8.15 (1H, d, J=1.25 Hz), 10.05 (1H, s),10.50 (1H, s); MS (ESI) m/z 287/289 (M−H)⁻.

[0246] Anal. for C₁₆H₁₀ClFO₂: Calc'd: C: 66.56H: 3.49 Found: C: 66.37H:3.65

EXAMPLE 1y 1-Chloro-6-(4-hydroxy-2-methylphenyl)-2-naphthol

[0247] The title compound was prepared by reacting1-chloro-6-(4-methoxy-2-methylphenyl)-2-naphthol (400 mg, 1.41 mmol)with boron tribromide (4.0 mL of 1.0 M solution in CH₂Cl₂, 4.0 mmol)according to method D to yield 310 mg (77%) of a yellowish solid: mp216-218° C.; ¹H NMR (DMDO-d₆): δ 2.20 (1H, s), 6.68 (1H, dd, J=8.19 Hz,J=2.42 Hz), 6.72 (1H, d, J=2.13 Hz), 7.10 (1H, d, J=8.16 Hz), 7.29 (1H,d, J=8.89 Hz), 7.29 (1H, d, J=8.89 Hz), 7.53 (1H, dd, J=8.78 Hz, J=1.62Hz), 7.76 (1H, d, J=1.38 Hz), 7.80 (1H, d, J=8.94 Hz), 8.02 (1H, d,J=8.72 Hz), 9.4 (1H, s), 10.43 (1H, s); 13 NMR (DMDO-d₆): δ 20.47,112.20, 112.99, 117.00, 118.66, 121.85, 127.83, 128.09, 128.38, 129.47,130.00, 130.88, 131.65, 136.09, 136.51, 150.88, 156.62; MS (ESI)m/z283/285(M−H)⁻.

[0248] Anal. for C₁₈H₁₅ClO₂: Calc'd: C: 71.71H: 4.60 Found: C: 71.30H:4.66

[0249] Synthesis of Compounds in Scheme 8

Intermediate 38 6-Methoxy-2-naphthalenyl)boronic Acid

[0250] In a 500 mL flask was added 2-bromo-6-methoxynaphthalene (8.02 g,33.8 mmol), anhydrous THF (125 mL), and a few crystals of1,10-phenanthroline as an indicator. The mixture was cooled to −78° C.and sec-butyllithium (56 mL of 1.3 N solution in hexanes, 72.8 mmol) wasslowly added via syringe. After stirring for 0.5 h triisopropyl borate(47 mL, 203.7 mmol) was added and the solution was stirred for 1 h at−78° C. and then allowed to warm to ambient temperature. Then ice cold 2N HCl (100 mL) was added and the mixture was stirred for 5 minutes afterwhich more 2 N HCl (100 mL) was added and stirred for another 5 minutes.The mixture was then extracted with ethyl acetate (3×), dried overMgSO₄, and concentrated to near dryness. Hexanes added to theconcentrate induced crystallization which was then collected byfiltration and then dried under vacuum to give 7.01 g (100%) of a lightorange powder. ¹H NMR (500 MHz, DMSO-d₆) δ 3.88 (3H, s), 7.15 (1H, dd,J=8.9 Hz, 2.7 Hz), 7.29 (1H, d, J=2.5 Hz), 7.75 (1H, d, J=8.3 Hz), 7.83(2H, appt), 8.30 (1H, s); MS (EI) m/z 202.17(M⁺).

Intermediate 39 2-Chloro-4-(6-methoxy-2-naphthyl)phenol

[0251] A mixture of 4-bromo-2-chlorophenol (730 mg, 3.5 mmol),(6-methoxy-2-naphthalenyl)boronic acid (780 mg, 3.85 mmol), sodiumcarbonate (930 mg as 2 N aqueous, 8.8 mmol), andtetrakis(triphenylphosphine)palladium(0) (203 mg, 0.18 mmol) in DME (45mL) was brought to reflux for 12 h. The reaction was then cooled,extracted with ethyl acetate (3×), dried over Na₂SO₄ and concentrated.Column chromatography (30% EtOAc/hexanes) produced 360 mg (30%) ofproduct as a white solid. mp 129-130° C.; ¹H NMR (300 MHz, DMSO-d₆) δ3.88 (3H, s), 7.08 (1H, d, J=8.2 Hz), 7.17 (1H, dd, J=8.6 Hz, 2.1 Hz),7.34 (1H, d, J=2.1 Hz), 7.59 (1H, dd, J=8.6 Hz, 2.1 Hz), 7.75 (2H, m),7.87 (1H, d, J=8.8 Hz), 7.88 (1H, d, J=8.6), 8.09 (1H, s), 10.34 (1H,s); MS m/z 283/285(CI pattern) (M−H⁺);

[0252] Anal. for C₁₇H₁₃ClO₂:: Calc'd: C: 71.71H: 4.60 Found: C: 71.68H:4.72

Intermediate 40 3-Chloro-4-(6-methoxy-2-naphthyl)phenol

[0253] The title compound was prepared by reacting4-bromo-3-chlorophenol (3.8 g, 18.3 mmol) with I12372-104 (4.81 g, 23.8mmol) according to method A to yield 5.09 g (98%) of white solid: mp139-142° C.; ¹H NMR (DMSO-d₆): δ 3.89 (3H,s), 6.87 (1H, dd, J=8.39 Hz,J=2.45 Hz), 6.98 (1H, J=2.40 Hz), 7.19 (1H, dd, J=8.98 Hz, J=2.46 Hz),7.32 (1H, d, J=8.39 Hz), 7.35 (1H, d, J=2.38 Hz), 7.50 (1H, dd, J=8.47Hz, J=1.73 Hz), 7.83-7.88 (3H, m), 10.04 (1H, s); MS (ESI) m/z2831285(M−H)⁻.

[0254] Anal. for C₁₆H₁₁ClO:: Calc'd: C: 71.71H: 4.60 Found: C: 71.50H:4.62

Intermediate 41 2,6-Difluoro-4-(6-methoxy-2-naphthyl)phenol

[0255] The title compound was prepared by reacting4-bromo-2,6-difluorophenol (3.5 g, 16.8 mmol) with intermediate 38 (4.2g, 20.2 mmol) according to method A to yield 1.1 g (23%) of white solid:mp 188-190° C.; ¹H NMR (DMSO-d₆): δ 3.89 (3H, s), 7.19 (1H, dd, J=8.92Hz, J=2.52 Hz), 7.34 (1H, J=2.41 Hz), 7.48-7.59 (2H, m), 7.80 (1H, dd,J=8.61 Hz, J=1.76 Hz), 7.88 (1H, d, J=8.65 Hz), 8.17 (1H, d, J=1.25 Hz),10.31 (1H, s); MS (ESI) m/z285 (M−H)⁻.

[0256] Anal. for C₁₇H₁₂F₂O₂:: Calc'd: C: 71.32H: 4.23 Found: C: 71.10H:4.17

Intermediate 42 4-(6-Hydroxy-2-naphthyl)-3-methoxyphenyl4-methylbenzenesulfonate

[0257] 4-Bromo-3-methoxyphenyl 4-methylbenzenesulfonate A mixture of4-bromo-resorcinol (4.92 g, 26.0 mmol), p-toluenesulfonic chloride (5.95g, 31.2 mmol), potassium carbonate (23 g, 167 mmol), and acetone (300mL) was refluxed for 16 hr. Iodomethane (9.89 g, 70 mmol) was added andthe mixture was refluxed for an additional 12 hr. The mixture was cooledto room temperature and ether (200 mL) was added and the suspension wasfiltered. The filtrate was stripped of solvent and purified on a silicacolumn (10% ethyl acetate—hexanes) to yield 6.49 g (70%) of the titlecompound as a white solid.

[0258]¹H NMR (CDCl₃): δ 2.45 (3H, s), 3.78 (3H, s), 6.40 (1H, dd, J=2.45Hz, J=8.60 Hz), 6.59 (1H, d, J=2.48 Hz), 7.33 (2H, d, J=8.30 Hz), 7.40(1H, d, J=8.69 Hz), 7.71 (2H, d, J=8.23 Hz); MS (ESI) m/z 355/357(M−H)⁻.

[0259] Anal. for C₁₄H₁₃BrO₄S: Calc'd: C: 47.07H: 3.67 Found: C: 47.14H:3.57

[0260] The title compound was prepared by reacting4-bromo-3-methoxyphenyl 4-methylbenzenesulfonate (3.07 g, 8.60 mmol) andtert-butyl[(2-(6-naphthyl boronic acid)oxy]dimethylsilane (2.86 g, 9.46mmol) according to method A to yield 2.15 g (53%) of an orange solid):

[0261]¹H NMR (CDCl₃): δ 2.44 (3H, s), 3.65 (3H, s), 6.69 (1H, dd, J=2.10Hz, J=8.29 Hz), 6.74 (1H, d, J=2.10 Hz), 7.06-7.11 (2H, m), 7.36 (1H, d,J=8.27 Hz), 7.45 69 (1H, dd, J=1.32 Hz, J=8.57 Hz), 7.51 (1H, d, J=8.28Hz), 7.67 (1H, d, J=8.61 Hz), 7.77 (1H, d, J=8.80 Hz), 7.80-7.85 (3H,m), 9.78 (1H, s); MS (ESI) m/z 419 (M−H)⁻.

[0262] Anal. for C₂₄H₂₀O₅S 0.25H₂O: Calc'd: C: 67.82H: 4.86 Found: C:67.75H: 4.56

EXAMPLE 1aa 6-(4-Hydroxy-2-methoxyphenyl)-2-naphthol

[0263] A solution of 4-(6-hydroxy-2-naphthyl)-3-methoxyphenyl4-methylbenzenesulfonate (1.74 g, 4.05 mmol), potassium hydroxide (5 g),water (85 mL), and ethanol (85 mL) was stirred at 90° C. for 2 hr. Thereaction was cooled to room temperature and concentrated to 50% volume,neutralized with acetic acid, and extracted with ethyl acetate (3×200mL). The combined organic layers were washed with brine, dried oversodium sulfate, filtered, evaporation of the solvent, and purificationby silica column (25% ethyl acetate—hexanes) yielded 1.01 g (94%) of thetitle compound as a tan solid. A sample was further purified bypreparative reverse phase HPLC to yield a tan solid: mp 152-154° C.;

[0264]¹H NMR (DMSO-d₆): δ 3.72 (3H, s), 6.46 (1H, dd, J=1.52 Hz, J=8.20Hz), 6.52 (1H, d, J=1.77 Hz), 7.04-7.09 (2H, m), 7.16 (1H, d, J=8.23Hz), 7.47 (1H, d, J=8.50 Hz), 7.63 (1H, d, J=8.57 Hz), 7.72-7.75 (2H,m), 9.56 (1H, bs), 9.68 (1H, bs); MS (ESI) m/z265 (M−H)⁻.

[0265] Anal. for C₁₇H₁₄O₃: Calc'd: C: 76.68H: 5.30 Found: C: 76.68H:5.30

EXAMPLE 1l 6-(3-Chloro-4-hydroxyphenol)-2-naphthol

[0266] A mixture of 2-chloro-4-(6-methoxy-2-naphthyl)phenol (192 mg,0.71 mmol) and pyridine hydrochloride (3 g, 26 mmol) was heated to 200°C. for 1 h while stirring. After allowing the mixture to cool, water wasadded to dissolve the solid and the aqueous layer was extracted withether (3×). The ether layers were combined, dried over Na₂SO₄ and passedthrough a silica plug. Evaporation under reduced pressure afforded 180mg (98%) of product as a tan colored solid. mp 176-177° C.; ¹H NMR (300MHz, DMSO-d₆) δ 7.09 (3H, m), 7.57 (1H, dd, J=7.6 Hz, 1.5 Hz), 7.70 (3H,m), 7.82 (1H, d, J=8.6 Hz), 8.02 (1H, s), 9.77 (1H, s), 10.28 (1H, s);MS m/z269/271 (Cl pattern) (M−H⁺);

[0267] Anal. for C₁₆H₁₁ClO₂: Calc'd: C: 70.99H: 4.10 Found: C: 70.64H:4.16

EXAMPLE 1ab 6-(2-Chloro-4-hydroxyphenyl)-2-naphthol

[0268] The title compound was prepared by reacting3-chloro-4-(6-methoxy-2-naphthyl)phenol (2.4 g, 8.43 mmol) with borontribromide (21.9 mL of 1.0 M solution in CH₂Cl₂, 21.9 mmol) according tomethod D to yield 2.1 g (92%) of a yellowish solid: mp 209-210° C.; ¹HNMR (DMDO-d₆): δ 6.86 (1H, dd, J=8.42 Hz, J=2.45 Hz), 6.97 (1H, d, 2.41Hz), 7.11 (1H, dd, J=8.78 Hz, J=2.35 Hz), 7.16 (1H, d, J=2.15 Hz), 7.30(1H, d, J=8.40 Hz), 7.42 (1H, dd, J=8.51 Hz, J=1.71 Hz), 7.71 (1H, d,J=8.59 Hz), 7.76 (1H, s), 7.80 (1H, d, J=8.82 Hz), 9.82 (1H, s), 10.01(1H,s); ¹³C NMR (DMDO-d₆): δ 108.45, 114.79, 116.21, 118.90, 125.53,127.43, 127.77, 127.92, 129.56, 130.70, 131.73, 132.34, 133.18, 133.52,155.56, 157.46; MS (ESI) m/z2691271 (M−H)⁻.

[0269] Anal. for C₁₆H₁₁ClO₂: Calc'd: C: 70.99H: 4.10 Found: C: 70.68H:4.09

EXAMPLE 1w 1-Chloro-6-(3-chloro-4-hydroxyphenyl)-2-naphthol

[0270] The title compound was prepared by reacting6-(3-chloro-4-hydroxyphenyl)-2-naphthol (500 mg, 1.85 mmol) and NCS (346mg, 2.59 mmol) in THF (37 mL) according to method A to yield 380 mg(68%) of yellowish solid: mp 174-175° C.; ¹H NMR (DMDO-d₆): δ 7.09 (1H,d, 8.47 Hz), 7.31 (1H, d, J=8.89 Hz), 7.60 (1H, dd, J=8.20 Hz, J=2.26Hz), 7.78 (1H, d, J=2.22 Hz), 7.84 (1H, d, J=8.99 Hz), 7.88 (1H, dd,J=9.00 Hz, J=1.80 Hz), 8.05 (1H, d, J=8.86 Hz), 8.14 (1H, d, J=1.60 Hz),10.37 (1H, s), 10.49 (1H, s);MS (ESI) m/z303/305/307 (M−H)⁻.

[0271] Anal. for C₁₆H₁₀Cl₂O₂: Calc'd: C: 62.98H: 3.30 Found: C: 62.65H:3.21

EXAMPLE 1ac 1-Chloro-6-(2-chloro-4-hydroxyphenyl)-2-naphthol

[0272] The title compound was prepared by reacting6-(2-chloro-4-hydroxyphenyl)-2-naphthol (500 mg, 1.85 mmol) and NCS (321mg, 2.40 mmol) in THF (40 mL) according to method C to yield 435 mg(77%) of yellowish solid: mp 224-226° C.; ¹H NMR (DMDO-d₆): δ 6.86 (1H,dd, J=8.42 Hz, J=2.41 Hz), 6.96 (1H, d, J=2.44 Hz), 7.30 (1H, d, J=3.19Hz), 7.33 (1H, d, J=2.65 Hz), 7.62 (1H, dd, J=8.81 Hz, J=1.71 Hz), 7.83(1H, d, J=8.93 Hz), 7.86 (1H, d, J=1.54 Hz), 8.04 (1H, J=8.76 Hz), 10.04(1H, s), 10.51 (1H, s); ¹³C NMR (DMDO-d₆): δ 112.24, 114.84, 116.26,118.79, 121.84, 128.16, 128.24, 128.35, 129.27, 130.03, 130.40, 131.73,132.38, 133.98, 151.24, 157.70; MS (ESI) m/z 303/305/307 (M−H)⁻.

[0273] Anal. for C₁₆H₁₀Cl₂O₂: Calc'd: C: 62.98H: 3.30 Found: C: 62.69H:3.36

EXAMPLE 1ba 1-Chloro-6-(3,5-difluoro-4-hydroxyphenyl)-2-naphthol

[0274] The title compound was prepared by reacting6-(3,5-difluoro-4-hydroxyphenyl)-2-naphthol (300 mg, 1.10 mmol) and NCS(155 mg, 1.16 mmol) in THF (30 mL) according to method C to yield 264 mg(78%) of grey solid: mp 209-210° C.; ¹H NMR (DMSO-d₆): δ 7.32 (1H, d,J=8.89 Hz), 7.50-7.61 (2H, m), 7.83 (1H, d, J=8.96 Hz), 7.92 (1H, dd.J=8.94 Hz, J=1.59 Hz), 8.05 (1H, d, J=8.88 Hz), 8.22 (1H, d, J=1.19 Hz),10.36 (1H, s), 10.54 (1H, s); MS (ESI) m/z305/307 (M−H)⁻.

[0275] Anal. for C₁₆H₉ClF₂O₂: Calc'd: C: 62.66H: 2.96 Found: C: 62.58H:3.09

[0276] Synthesis of Compounds in Scheme 9

Intermediate 43 6-Bromo-1-chloro-naphthalen-2-ol

[0277] The title compound was prepared by reacting 6-bromo-2-naphthol (3g, 13.4 mmol) and NCS (2.47 g, 18.5 mmol) in THF (50 mL) according tomethod C to yield 2.2 g (64%) of yellow solid: ¹H NMR (DMDO-d₆): δ 7.34(1H, d, J=8.87 Hz), 7.69 (1H, dd, J=1.75 Hz, J=6.09 Hz), 7.79 (1H, d,J=8.96 Hz), 7.96 (1H, d, J=9.03 Hz), 8.17 (1H, d, J=1.75 Hz), 10.68(1H,s); MS (ESI) m/z255/2571259 (M−H)⁻.

EXAMPLE 1m 1-Chloro-6-phenyl-2-naphthol

[0278] The title compound was prepared by reacting6-bromo-1-chloro-naphthalen-2-ol (300 mg, 1.17 mmol) with phenylboronicacid (170.7 mg, 1.40 mmol) according to method A to yield 240 mg (81%)of white solid: mp 135-137° C.; ¹H NMR (DMDO-d₆): δ 7.33 (1H, d, J=8.85Hz), 7.39 (1H, td, J=7.25 Hz, J=0.75 Hz), 7.51 (2H, t, J=7.59 Hz), 7.80(2H, d, J=7.63 Hz), 7.88 (1H, d, J=8.96 Hz), 7.93 (1H, dd, J=8.85 Hz,J=1.19 Hz), 8.10(1H, d, J=8.84 Hz), 8.20 (1H, s), 10.53 (1H, s); MS(ESI) m/z253/255 (M−H)⁻.

[0279] Anal. for C₁₆H₁₁ClO: Calc'd: C: 75.45H: 4.35 Found: C: 75.16H:4.17

Intermediate 44 6-Bromo-1-nitro-2-naphthol

[0280] 4-Nitro-4-methyl-2,3,5,6-tetrabromo-2,5-cyclohexadien-1-one (2.53g, 4.95 mmol, purity: 82.6%) was added to 6-bromo-2-naphthol (1 g, 4.5mmol) in 40 mL of dry ether. The reaction was allowed to react for 1.5hr at room temperature. The solid was filtered to give2,3,5,6-tetrabromo-4-methyl-phenol (144 mg). The solution was thenevaporated under vacuum. The crude mixture was dissolved in ethylacetate and washed with water. The organic layer was dried overanhydrous Na₂SO₄ and filtered and the solvent removed under vacuum.2,3,5,6-tetrabromo-4-methyl-phenol (1.2 g) was separated byrecrystallization of the crude product with ethyl acetate—hexane. Themother liquid was concentrated onto Florosil and purified on a silicacolumn (15%-20% ethyl acetate-hexane) to yield 0.731 g (61%) of thetitle compound as a yellow solid: mp 111-113° C.; ¹H NMR (DMDO-d₆): δ7.39 (1H, d, J=9.07 Hz), 7.54 (1H, d, J=9.05 Hz), 7.75 (1H, dd, J=9.05Hz, J=1.70 Hz), 8.03 (1H, d, J=9.14 Hz), 8.29 (1H, d, J=1.84 Hz), 11.65(1H, s); MS (ESI) m/z 266/268 (M−H)⁻; IR 1350 cm⁻¹, 1490 cm⁻¹.

[0281] Anal. for C₁₀H₆BrNO₃ 0.18H₂O: Calc'd: C: 44.27H: 2.36 N: 5.16Found: C: 44.24H: 2.14 N: 4.76.

Intermediate 456-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-1-nitro-2-naphthol

[0282] The title compound was prepared by reacting6-bromo-1-nitro-2-naphthol (560 mg, 2.1 mmol) with4-tert-butyl-dimethylsilyoxyboronic acid (688 mg, 2.73 mmol) accordingto method A to yield 347 mg (42%) of yellowish solid: ¹H NMR (DMDO-d₆):δ 0.23 (6H, s), 0.98 (9H, s), 6.99(2H, d, J=8.47 Hz), 7.35 (1H, d,J=9.05 Hz), 7.64 (1H, d, J=8.86 Hz), 7.70 (2H, d, J=8.51 Hz), 7.94 (1H,dd, J=6.62 Hz, J=1.25 Hz), 8.08 (1H, d, J=9.16 Hz), 8.22(1H, s), 11.45(1H, s); MS (ESI) m/z 394 (M−H)⁻.

EXAMPLE 1x 6-(4-Hydroxyphenyl)-1-nitro-2-naphthol

[0283] To a solution of6-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-1-nitro-2-naphthol (302mg, 0.764 mmol) in THF (12 mL) was added TBAF (0.92 mL, 0.917 mmol, 1.0M solution in THF). The solution was stirred for 10 minutes at roomtemperature, poured in water. The mixture was extracted with ethylacetate. The combined organic layers were washed with brine, driedanhydrous Na₂SO₄, filtered, evaporation of the solvent, and purificationon a silica column (20%-40% ethyl acetate-hexane) yielded 130 mg (61%)of a orange solid. An analytical sample was further purified byrecrystallization with ethyl acetate-hexane to yield the title compoundas a orange solid:: mp 199-201° C.; ¹H NMR (DMDO-d₆): δ 6.89(2H, d,J=8.51 Hz), 7.33 (1H, d, J=9.05 Hz), 7.62 (1H, d, J=8.94 Hz), 7.63(2H,d, 8.48 Hz), 7.91 (1H, dd, J=8.87 Hz, J=1.59 Hz), 8.06 (1H, d, 9.18 Hz),8.17 (1H, d, J=1.31 Hz), 9.64(1H, s), 11.40 (1H,s); MS (ESI) m/z280(M−H)⁻.

[0284] Anal. for C₁₆H₁₁NO₄: Calc'd: C: 68.32H: 3.94 N: 4.98 Found: C:67.91H: 4.06 N: 4.60

[0285] Synthesis of Compounds in Scheme 10

Intermediate 52 2-(2,5-Difluoro-4-methoxyphenyl)-6-methoxynaphthalene

[0286] The title compound was prepared by reacting4-bromo-2,5-difluoroanisole (4.06 g, 18.3 mmol) with intermediate 38(4.81 g, 23.8 mmol) according to method A to yield 5.18 g (94.2%) ofwhite solid: mp 153-155° C.; ¹H NMR (DMSO-d₆): δ 3.90 (3H, s), 3.91 (3H,s), 7.20 (1H, dd, J=8.94 Hz, J=2.50 Hz), 7.28 (1H, dd, J=12.38 Hz,J=7.47 Hz), 7.36 (1H, d, J=2.42 Hz), 7.56 (1H, dd, J=12.17 Hz, J=7.53Hz), 7.62-7.66 (1H, m), 7.89 (2H, d, J=8.67 Hz), 8.02 (1H, s); MS (ESI)m/z 301 (M−H)⁺; HRMS: calcd for C₁₈H₁₄F₂O₂, 300.0962; found (Cl(ISOBUTANE)), 300.0953

[0287] Anal. for C₁₈H₁₄F₂O₂: Calc'd: C: 71.99H: 4.70 Found: C: 73.00H:4.62

Intermediate 53 2-(2,6-Difluoro-4-methoxyphenyl)-6-methoxynaphthalene

[0288] The title compound was prepared by reacting4-bromo-3,5-difluoroanisole (4.06 g, 18.3 mmol) with intermediate 38(4.43 g, 22.0 mmol) according to method A to yield 3.4 g (62%) of whitesolid: mp 130-132° C.; ¹H NMR (acetone-d₆): δ 3.91 (3H, s), 3.94 (3H,s), 6.72-6.80 (2H, m), 7.20 (1H, dd, J=8.97 Hz, J=2.54 Hz), 7.35 (1H, d,J=2.48 Hz), 7.48-7.52 (1H, m), 7.85-7.90 (3H, m); MS (ESI) m/z301(M−H)⁺.

[0289] Anal. for C₁₈H₁₄F₂O₂: Calc'd: C: 71.99H: 4.70 Found: C: 71.67H:4.81

Intermediate 50 Trifluoro-methanesulfonic Acid 2-fluoro-4-methoxy-phenylEster 2-Fl uoro-4-methoxy-phenol

[0290] A mixture of 4-bromo-2-fluorophenol (8 g, 41.9 mmol), CuBr (6.0g, 41.9 mmol), sodium methoxide (95.8 mL of 4.4 M in methanol), and DMF(200 mL) were heated at 150° C. for 4 hr. The reaction mixture wascooled to room temperature, poured into HCl (419 mL of 2N aqueoussolution), filtered through celite and then extracted with ethylacetate. The combined organic layers were washed with sodium bicarbonatesolution, dried over sodium sulfate, filtered, evaporation of thesolvent, and purification by silica column chromatography (5%-15% ethylacetate—hexane) yielded 5.63 g (95%) of the title compound as ayellowish oil: ¹H NMR (DMDO-d₆): δ 3.67 (3H,s), 6.55 (1H, m), 6.78 (1H,dd, J=12.97 Hz, J=2.95 Hz), 6.85 (1H, dd, J=10.14 Hz, J=8.87 Hz), 9.24(1H, s) 3.67 (3H,s)

[0291] The title compound was prepared by reacting2-fluoro-4-methoxy-phenol (2.8 g, 19.7 mmol) withtrifluoromethanesulfonic anhydride (4.31 mL, 7.23 g, 25.6 mmol)according to method B to yield 3.86 g (68%) of a clear yellow oil. ¹HNMR (DMSO-d₆): δ 3.82 (3H, s), 6.89-6.94 (1H, m), 7.24 (1H, dd, J=12.49Hz, J=2.98 Hz), 7.61 (1H, t, J=9.09 Hz).

Intermediate 54 2-(2-Fluoro-4-methoxyphenyl)-6-methoxynaphthalene

[0292] The title compound was prepared by reactingtrifluoro-methanesulfonic acid 2-fluoro-4-methoxy-phenyl ester (3.86 g,14.0 mmol) with intermediate 38 (2.97 g, 14.8 mmol) according to methodA to yield 2.27 g (58%) of white solid: mp 104-106° C.;

[0293]¹H NMR (DMSO-d₆): δ 3.83 (3H, s), 3.89 (3H, s), 6.92 (1H, dd,J=8.46 Hz, J=2.64 Hz), 6.98 (1H, dd, J=12.92, J=2.48 Hz), 7.19 (1H, dd,J=8.94 Hz, J=2.46 Hz), 7.35 (1H, J=2.38 Hz), 7.53-7.63 (2H, m), 7.90(2H, d, J=8.72 Hz), 7.97 (1H, s); MS (ESI) m/z 283 (M+H⁺).

[0294] Anal. for C₁₈H₁₅FO₂: Calc'd: C: 76.58H: 5.36 Found: C: 76.30H:5.23

EXAMPLE 1ar 2-Chloro-4-(2-naphthyl)phenol

[0295] A mixture of 4-bromo-2-chlorophenol (1.45 g, 6.98 mmol),2-naphthaleneboronic acid (1.0 g, 5.81 mmol), sodium carbonate (1.54 gas 2 N aqueous, 14.53 mmol), andtetrakis(triphenylphosphine)palladium(0) (340 mg, 0.3 mmol) in DME (70mL) was brought to reflux for 6 h according to Method A. The reactionwas then cooled, extracted with ethyl acetate (3×), dried over Na₂SO₄and concentrated. Column chromatography (30% ethyl acetate-hexanes)produced 610 mg (34%) of product as a white solid. An analytical samplewas prepared by reverse phase HPLC (CH₃CN/H₂O, 0.1% TFA). mp 99.5-100.0°C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.10 (1H, d, J=8.4 Hz), 7.52 (2H, m),7.63 (1H, dd, J=8.5 Hz, 2.0 Hz), 7.81 (2H, m), 7.95 (3H, m), 8.17 (1H,s), 10.40 (1H, s); MS m/z 253/255 (Cl pattern) (M−H⁺);

[0296] Anal. for C₁₆H₁₁ClO: Calc'd: C: 75.45H: 4.35 Found: C: 75.24H:4.34

EXAMPLE 1z 6-(4-Hydroxy-2-methylphenyl)-2-naphthol

[0297] The title compound was prepared by reacting6-(4-methoxy-2-methylphenyl)-2-naphthol (420 mg, 1.59 mmol) with borontribromide (4.53 mL of 1.0 M solution in CH₂Cl₂, 4.53 mmol) according tomethod D to yield 400 mg (quantitative yield) of a yellowish solid: mp191-193° C.; ¹H NMR (DMDO-d₆): δ 6.68 (1H, dd, J=8.41 Hz, J=2.21 Hz),6.72 (1H, d, J=2.21 Hz), 7.07-7.11 (2H, m), 7.14 (1H, d, J=2.21 Hz),7.33 (1H, dd, J=8.41 Hz, J=2.21 Hz), 7.64 (1H, d, J=0.885 Hz), 7.68 (1H,d, J=8.41 Hz), 7.77 (1H, d, J=9.29 Hz), 9.33 (1H, s), 9.69 (1H, s); ¹³CNMR (DMDO-d₆): δ 108.34, 112.82, 116.84, 118.68, 125.47, 127.13, 127.56,128.02, 129.26, 130.71, 132.26, 133.02, 135.63, 135.90, 155.11, 156.31;MS (ESI) m/z 249 (M−H)⁺.

[0298] Anal. for C₁₇H₁₄O₂: Calc'd: C: 81.58H: 5.64 Found: C: 81.36H:5.53

EXAMPLE 1ad 6-(2-Fluoro-4-hydroxyphenyl)-2-naphthol

[0299] The title compound was prepared by2-(2-fluoro-4-methoxyphenyl)-6-methoxynaphthalene (1.12 g, 3.97 mmol)with boron tribromide (23.8 mL of 1.0 M solution in CH₂Cl₂, 23.8 mmol)according to method D to yield 0.92 g (91%) of a white solid: mp208-209° C.; ¹H NMR (DMSO-d₆): δ 6.66-6.75 (2H, m), 7.08-7.13 (2H, m),7.41 (1H, dd, J=9.37 Hz, J=8.57 Hz), 7.49-7.53 (1H, m), 7.72 (1H, d,J=8.64 Hz), 7.80 (1H, d, J=8.76 Hz), 7.86 (1H, s), 9.79 (1H, s), 10.01(1H, s); MS (ESI) m/z255 (M+H)⁺, MS (ESI) m/z253 (M−H)⁻.

[0300] Anal. for C₁₆H₁₁FO₂ 0.15H₂O: Calc'd: C: 74.79H: 4.43 Found: C:74.79H: 4.23

EXAMPLE 1ae 6-(2,5-Difluoro-4-hydroxyphenyl)-2-naphthol

[0301] The title compound was prepared by2-(2,5-difluoro-4-methoxyphenyl)-6-methoxynaphthalene (1.5 g, 5.0 mmol)with boron tribromide (25 mL of 1.0 M solution in CH₂Cl₂, 25 mmol)according to method D to yield 1.28 g (94%) of a yellowish solid: mp217-219° C.; ¹H NMR (DMSO-d₆): δ 6.90 (1H, dd, J=11.87 Hz, J=7.51 Hz),7.10-7.15 (2H, m), 7.45 (1H, dd, J=11.87, J=7.61 Hz), 7.53-7.55 (1H, m),7.74 (1H, d, J=8.65 Hz), 7.92 (1H, s), 9.85 (1H, s), 10.50 (1H, s); MS(ESI) m/z271 (M−H)⁻.

[0302] Anal. for C₁₆H₁₀F₂O₂: Calc'd: C: 70.59H: 3.70 Found: C: 70.35H:3.65

EXAMPLE 1af 6-(2,6-Difluoro-4-hydroxyphenyl)-2-naphthol

[0303] The title compound was prepared by reacting2-(2,6-difluoro-4-methoxyphenyl)-6-methoxynaphthalene (1.5 g, 5.0 mmol)with boron tribromide (25 mL of 1.0 M solution in CH₂Cl₂, 25 mmol)according to method D to yield 1.35 g (99%) of a yellowish solid:mp>240° C.; ¹H NMR (DMSO-d₆): δ 6.55-6.63 (2H, m), 7.11 (1H, dd, J=8.76Hz, J=2.34 Hz), 7.15 (1 h, d, J=2.05 Hz), 7.36 (1H, dd, J=8.58 Hz,J=1.34 Hz), 7.39 (1H, d, J=8.83 Hz), 7.79 (1H, s), 7.80 (1H, d, J=8.74Hz), 9.85 (1H, s), 10.48 (1H, s); MS (ESI) m/z271 (M−H)⁻; MS (ESI)m/z543 (2M−H)⁻.

[0304] Anal for C₁₆H₁₀F₂O₂: Calc'd: C: 70.59H: 3.70 Found: C: 70.19H:3.58

EXAMPLE 1ag 1-Chloro-6-(2-fluoro-4-hydroxyphenyl)-2-naphthol

[0305] The title compound was prepared by reacting6-(2-fluoro-4-hydroxyphenyl)-2-naphthol (300 mg, 1.18 mmol) and NCS (191mg, 1.43 mmol) in THF (30 mL) according to method C to yield 170 mg(50%) of yellowish solid: mp 179-180° C.; ¹H NMR (DMSO-d₆): δ 6.73 (1H,dd, J=12.69 Hz, J=2.44 Hz), 6.75 (1H, dd, J=8.30 Hz, J=2.44 Hz), 7.31(1H, d, J=8.79 Hz), 7.45 (1H, t, J=9.28 Hz), 7.70-7.72 (1H, m), 7.83(1H, d, J=8.79 Hz), 7.97 (1H, s), 8.06 (1H, d, J=7.79 Hz), 10.06 (1H,s), 10.48 (1H, s); MS (ESI) m/z287/289 (M−H)⁻.

[0306] Anal. for C₁₆H₁₀ClFO₂: Calc'd: C: 66.56H: 3.49 Found: C: 66.45H:3.52

EXAMPLE 1ah 1-Chloro-6-(2,5-difluoro-4-hydroxyphenyl)-2-naphthol

[0307] The title compound was prepared by reacting6-(2,5-difluoro-4-hydroxyphenyl)-2-naphthol (500 mg, 1.84 mmol) and NCS(295 mg, 2.21 mmol) in THF (37 mL) according to method C to yield 370 mg(66%) of yellowish solid: mp 203-204° C.; ¹H NMR (DMSO-d₆): δ 6.90 (1H,dd, J=11.90 Hz, J=7.50 Hz), 7.32 (1H, d, J=8.88 Hz), 7.49 (1H, dd,J=11.87 Hz, J=7.60 Hz), 7.72-7.76 (1H, m), 7.84 (1H, d, J=8.97 Hz), 8.03(1H, s), 8.06 (1H, d, 8.87 Hz), 10.58 (2H, s); MS (ESI) m/z3051307(M−H)⁻; HRMS calcd for C₁₆H₉ClF₂O₂ 306.02591, observed 305.01863 (M−H)⁻.

[0308] Anal. for C₁₆H₉ClF₂O₂.0.4H₂O: Calc'd: C: 61.22H: 3.15 Found: C:61.29H: 3.17

EXAMPLE 1ai 1-Chloro-6-(2,6-difluoro-4-hydroxyphenyl)-2-naphthol

[0309] The title compound was prepared by reacting6-(2,6-difluoro-4-hydroxyphenyl)-2-naphthol (510 mg, 1.86 mmol) and NCS(301 mg, 2.25 mmol) in THF (30 mL) according to Method C to yield 440 mg(77%) of yellowish solid: mp 213-214° C.;

[0310]¹H NMR (acetone-d₆): δ 6.71-6.78 (2H, m), 7.47 (1H, d, J=8.85 Hz),7.76 (1H, dd, J=8.12 Hz, J=1.52 Hz), 7.97 (1H, d, J=8.90 Hz), 8.04 (1H,s), 8.29 (1H, d, J=8.80 Hz), 9.26 (1H, s), 9.60 (1H, s); MS (ESI)m/z3051307 (M−H); HRMS: calcd for C₁₆H₉ClF₂O₂, 306.0259; found (ESI—),306.01991 Anal. for C₁₆H₉ClF₂O₂.0.25H₂O:

[0311] Calc'd: C: 61.75H: 3.08 Found: C: 61.75H: 2.90

[0312] Synthesis of Compounds in Scheme 11

Intermediate 56 N-(7-hydroxynaphthyl)acetamide

[0313] To a solution of 8-amino-2-naphthol (149.1 g, 0.937 mol) inmethanol (1L) was added acetic anhydride (93 mL, 0.984 mol). Thereaction was refluxed for 90 minutes and cooled to room temperature. Thesolvent was removed and the residue was filtered through a plug ofsilica with ethyl acetate. The solvent was removed to yield 175.8 g(93%) of the title compound as a dark purple solid. An analytical samplewas further purified by reverse phase preparative HPLC to yield a pinksolid: mp 161-162° C.; ¹H NMR (DMSO-d₆): δ 2.15 (3H, s), 7.09 (1H, dd,J=1.95 Hz, J=8.79 Hz), 7.20-7.26 (2H, m), 7.49 (1H, d, J=7.31 Hz), 7.63(1H, d, J=8.11 Hz), 7.77 (1H, d, J=8.81 Hz), 9.76 (1H, s), 9.79 (1H, s);MS (ESI) m/z202 (M+H)⁺.

[0314] Anal. for C₁₂H₁₁NO₂: Calc'd: C: 71.63H: 5.51 N: 6.96 Found: C:71.21H: 5.45 N: 6.89

Intermediate 57 N-(7-methoxynaphthyl)acetamide

[0315] To a mixture of N-(7-hydroxynaphthyl)acetamide (175.4 g, 0.872mol), potassium carbonate (301 g, 2.18 mol), and acetone (1 l) was addediodomethane (270 mL, 4.36 mol). The reaction mixture was refluxed for 6hr, cooled to room temperature, and the solvent removed. The residue wasfiltered through silica with ethyl acetate and triturated with ethylacetate to yield 161.6 g (86%) of a gray solid. An analytical sample wasfurther purified by preparative reverse phase HPLC to yield the titlecompound as a white solid: mp 154-155° C.; ¹H NMR (DMSO-d₆): δ 2.19 (3H,s), 3.90 (3H, s), 7.19 (1H, dd, J=2.39 Hz, J=8.94 Hz), 7.29-7.34 (2H,m), 7.39 (1H; d, J=1.86 Hz), 7.75-7.68 (2H, m), 7.87 (1H, d, J=8.96 Hz),9.82 (1H, s); MS (ESI) m/z 216 (M+H)⁺.

[0316] Anal. for C₁₃H₁₃NO₂: Calc'd: C: 72.54H: 6.09 N: 6.51 Found: C:72.24H: 6.43 N: 6.52.

Intermediate 58 7-Methoxynaphthylamine

[0317] A mixture of N-(7-methoxynaphthyl)acetamide (160.6 g, 0.747 mol)and HCl (1.5 l of 1 N solution) was refluxed for 5 hr. The cooledreaction was neutralized with solid sodium bicarbonate and extractedwith dichloromethane until UV clear. The combined organic layers werefiltered through silica and evaporation of the solvent yielded 89.5 g(69%) of a brown solid. An analytical sample was prepared by preparativeHPLC to yield the title compound as a white solid: mp 134-136° C.; ¹HNMR (CDCl₃): δ 3.94 (3H, s), 4.01 (2H, bs), 6.80 (1H, d, J=7.26 Hz),7.05 (1H, d, J=2.20 Hz), 7.12-7.19 (2H, m), 7.28 (1H, d, J=8.17 Hz),7.71 (1H, d, J=8.93 Hz); MS (ESI) m/z 174 (M+H)⁺.

[0318] Anal. for C₁₁H₁₁NO CF₃CO₂H: Calc'd: C: 54.55H: 3.87 N: 4.89Found: C: 54.39H: 4.28 N: 4.78.

Intermediate 59 1-Fluoro-7-methoxynaphthalene

[0319] To a mixture of 7-methoxynaphthylamine (10.94 g, 63.24 mmol), HCl(15.8 mL of 12 N solution, 190 mmol), and water (50 mL) cooled to 10° C.was added a solution of sodium nitrite (4.58 g, 66.40 mmol) in water (25mL) over ten minutes. The solution was stirred for 30 minutes andcombined with fluoroboric acid (100 mL). The resulting green solid wascollected by filtration, washed first with water, then with ethanol, andthen with ether to yield a yellow solid [15.48 g (90%) of theuncharacterized diazonium fluoroborate salt intermediate]. This yellowsolid was combined with xylenes (250 mL) and refluxed for 1 hour. Thesolvent was removed and the residue was partitioned between ethylacetate and sodium bicarbonate solution. The organic layer was driedover sodium sulfate, filtered, evaporation of the solvent, andpurification on silica (hexanes) yielded the title compound as a lightyellow liquid. ¹H NMR (CDCl₃): δ 3.94 (3H, s), 7.10-7.28 (3H, m), 7.34(1H, d, J=2.50 Hz), 7.55 (1H, d, J=8.12 Hz), 7.75 (1H, dd, J=1.69 Hz,J=9.00 Hz); MS (EI) m/z 176 (M)⁺.

[0320] Anal. for C₁₁H₉FO: Calc'd: C: 74.99H: 5.15 Found: C: 74.84H: 5.14

Intermediate 60 8-Chloro-2-methoxynaphthalene

[0321] CuCl₂ (4.6 g, 24.6 mmol) and t-butyl nitrite (4.46 g, 43.3 mmol)were added to acetonitrile (125 mL) at 0° C. To this mixture was slowlyadded a solution of 7-methoxynaphthylamine (4.99 g, 28.8 mmol) inacetonitrile (25 mL). The reaction was allowed to warm to roomtemperature, stirred with HCl (400 mL of 2N solution) and extracted withethyl acetate (3×200 mL). The combined organic layers were washed with2N HCl, dried over sodium sulfate, filtered, evaporation of the solvent,and purification on a silica column (hexanes) yielded 2.27 g (41%) of anorange liquid. An analytical sample was further purified by reversephase preparative HPLC to yield the title compound as a yellow solid: mp32-34° C.;¹H NMR (CDCl₃): δ 3.98 (3H, s), 7.20 (1H, dd, J=2.52 Hz,J=8.96 Hz), 7.22-7.27 (1H, m), 7.52 (1H, d, J=2.47 Hz), 7.55 (1 h, d,J=7.47 Hz), 7.69 (1H, d, J=8.15 Hz), 7.75 (1H, d, J=8.95 Hz); MSm/z1911193 (M−H)⁻.

[0322] Anal. for C₁₁H₉ClO: Calc'd: C: 68.58H: 4.71 Found: C: 68.35H:4.85

Intermediate 61 1-Bromo-7-methoxy-naphthalene

[0323] To a solution of CuBr₂ (15.7 g, 70.3 mmol) and TBN (9.05 g, 87.9mmol) in acetonitrile (250 mL) at 0° C. was slowly added a solution of2-methoxynaphthylamine (10.14 g, 58.6 mmol) in acetonitrile (60 mL). Thedark solution was stirred at 0° C. for 2.5 hr, concentrated onto silica,and purified on a silica column to yield 4.03 g (29%) of a white solid.An analytical sample was further purified by preparative reverse phaseHPLC to yield the title compound as a white solid: mp 54-58° C.; ¹H NMR(CDCl₃): δ 3.97 (3H, s), 7.15-7.21 (2H, m), 7.50 (1H, d, J=2.42 Hz),7.71-7.76 (3H, m); MS (EI) m/z236 (M)⁺.

[0324] Anal. for C₁₁H₉BrO: Calc'd: C: 55.72H: 3.83 Found: C: 55.58H:3.60

Intermediate 62 7-Methoxy-1-naphthonitrile

[0325] A mixture of 1-bromo-7-methoxy-naphthalene (3.26 g, 13.8 mmol),Zn(CN)₂ (2.26 g, 19.2 mmol), and tetrakis(triphenylphosphine)palladium(1.6 g, 1.4 mmol) in DMF (50 mL) was stirred at 120° C. for 15 hr. Thecooled reaction mixture was poured into 200 mL 1 N NH₄Cl solution andextracted with ethyl acetate (3×350 mL). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered, evaporationof the solvent, and purification on a silica column (10% ethylacetate—hexanes) yielded 1.28 g (51%) of the title compound as a whitesolid: mp 62-66° C.; ¹H NMR (DMSO-d₆): δ 4.00 (3H, s), 7.25 (1H, dd,J=2.48 Hz, J=8.96 Hz), 7.36-7.47 (1H, m), 7.47 (1H, d, J=2.39 Hz), 7.81(1H, d, J=9.00 Hz), 7.88 (1H, dd, J=0.81 Hz, J=7.23 Hz), 8.00 (1H, d,J=8.21 Hz); MS (EI) m/z 183 (M)⁺;

[0326] (no indentation)Anal. for C₁₂H₉NO: Calc'd: C: 78.67H: 4.95 N:7.65 Found: C: 78.83H: 4.60 N: 6.80.

Intermediate 64 7-Methoxy-3,4-dihydronaphthalene-1-carbonitrile

[0327] To a mixture of 7-methoxy-1-tetralone (39.65 g, 0.23 mol), zinciodide (1.73 g, 5.4 mmol), and benzene (100 mLs) was addedtrimethylsilylcyanide (25.0 g. 0.25 mol). The mixture was stirredovernight at room temperature. Pyridine (350 mL) was added andphosphorous oxychloride (100 mL) was then added dropwise, with a slighttemperature increase. The mixture was heated to reflux and held for 6hr. TLC showed one mid-Rf spot for the desired product. The mixture wasstirred overnight at room temperature. The mixture was carefully pouredonto ice/hydrochloric acid (about 1.5 liter of 10% HCl). The totalvolume was 2 liters. This mixture was extracted with ethyl acetate(3×500 mLs), the organics combined and washed with water (2×500 mLs) andthen brine (500 mLs). The ethyl acetate was dried over magnesium sulfateand evaporated off provide a liquid which on standing solidified. Thiscrude solid was slurried in hexane and filtered to give 31.3 g (74%) ofa tan solid. Some of this material was purified by silica gelchromatography (10% ethyl acetate-hexanes) to provide a solid: mp 47-49°C.; ¹H NMR (DMSO-d₆): δ 2.44-2.50 (2H, m), 2.72 (2H, t, J=8.4 Hz), 6.81(1H, d, J=2.6 Hz), 6.90 (1H, dd, J=2.9 Hz, J=8.2 Hz), 7.17-7.19 (2H, m);MS m/z 168 ([M−H]−);

[0328] Anal. for C₁₂H₁₁NO: Calc'd: C: 77.81H: 5.99 N: 7.56 Found: C:77.71H: 5.69 N: 7.50

Intermediate 62 7-Methoxy-1-cyanonaphthalene

[0329] To a mixture of 7-methoxy-3,4-dihydronaphthalene-1-carbonitrile(9.95 g, 53.1 mmol) in p-cymene (100 mLs) was added 10% Pd/C (5 g), thereaction mixture was stirred and heated to 150° C. overnight. Themixture was cooled and the catalyst removed by filtering through filteraid. The p-cymene was removed on the rotovap with the vacuum pump,giving a liquid which solidified on standing. The solid was slurried inhexane, filtered and dried to afford a white solid (4.3 g, 44%). Aportion was purified further by silica gel (10% ethyl acetate-hexanes)to produce a white solid: mp 77-78° C.;

[0330]¹H NMR (DMSO-d₆): δ3.97 (3H, s), 7.36 (1H, s), 7.39 (1H, d, J=2.5Hz), 7.52 (1H, t, J=7.4 Hz), 8.04-8.13 (2H, m), 8.24 (1H, d, J=8.2 Hz).

[0331] Anal. for C₁₂H₉NO: Calc'd: C: 78.67H: 4.95 N: 7.51 Found: C:78.47H: 4.73 N: 7.51

[0332] Synthesis of Compounds in Scheme 12

Intermediate 65 8-Fluoro-2-naphthol

[0333] The title compound was prepared by reacting1-fluoro-7-methoxynaphthalene (7.99 g, 45.34 mmol) with boron tribromide(68 mL of 1 N solution, 68 mmol) according to method D to yield 3.99 g(54%) of a red solid. An analytical sample was prepared by preparativereverse phase HPLC to yield a white solid: mp 89-92° C.;

[0334]¹H NMR (DMSO-d₆): δ 7.16 (1H, dd, J=2.42 Hz, J=8.90 Hz), 7.21-7.25(3H, m), 7.62-7.65 (1H, m), 7.85 (1H, dd, J=1.72 Hz, J=8.87 Hz), 10.08(1H, s); MS (ESI) m/z 161 (M−H)⁻.

[0335] Anal. for C₁₀H₇FO: Calc'd: C: 74.07H: 4.35 Found: C: 73.90H: 4.30

Intermediate 66 8-Chloro-2-naphthol

[0336] The title compound was prepared by reacting8-chloro-2-methoxynaphthalene (10.25 g, 53.4 mmol) with boron tribromide(67 mL of 1 N solution, 67 mmol) according to method D to yield 8.76 g(92%) of a yellow solid. An analytical sample was further purified byreverse phase preparative HPLC to yield the title compound as a whitesolid: mp 95-100° C.; ¹H NMR (DMSO-d₆): δ 7.18 (1H, dd, J=2.37 Hz,J=8.85 Hz), 7.23-7.28 (1H, m), 7.41 (1H, d, J=2.28 Hz), 7.59 (1H, d,J=7.37 Hz), 7.81 (1H, d, J=8.15 Hz), 7.87 (1H, d, J=8.86 Hz), 10.17 (1H,s); MS m/z177/179 (M−H)⁻.

[0337] Anal. for C₁₀H₇ClO: Calc'd: C: 67.24H: 3.95 Found: C: 66.99H:4.06

Intermediate 67 7-Hydroxy-1-naphthonitrile

[0338] The title compound was prepared by reacting7-methoxy-1-naphthonitrile (1.19 g, 6.50 mmol) with pyridinium HCl (9 g)according to method D to yield 0.88 g (80%) of a white solid: mp184-188° C.; ¹H NMR (DMSO-d₆): δ 7.25 (1H, dd, J=2.30 Hz, J=8.88 Hz),7.38 (1H, d, J=2.20 Hz), 7.39-7.44 (1H, m), 7.98 (1H, d, J=8.91 Hz),8.04 (1H, d, J=7.14 Hz), 8.17 (1H, d, J=8.19 Hz), 10.48 (1H, s); MS(ESI) m/z 170 ([M+H]+); MS (ESI) m/z 168 (M−H)⁻.

[0339] Anal. for C₁₁H₇NO: Calc'd: C: 78.09H: 4.17 N: 8.28 Found: C:77.99H: 3.99 N: 8.47.

Intermediate 68 6-Bromo-8-fluoro-2-naphthol

[0340] To a solution of 8-fluoro-2-naphthol (3.24 g, 20.0 mmol) inglacial acetic acid (30 mL) was slowly added a solution of bromine (7.35g, 46.0 mmol) in glacial acetic acid (30 mL). The solution was stirredat 100° C. for 1 hour. The reaction was cooled to room temperature,poured into water (50 mL) and extracted with ethyl acetate (3×150 mL).The combined organic layers were washed with sodium bicarbonatesolution, dried over sodium sulfate, filtered, evaporation of thesolvent, and purified on a silica column (2.5% ethyl acetate—hexanes) toyield 3.96 g (12.4 mmol, 62%) of the intermediate1,6-dibromo-8-fluoro-2-naphthol as a yellow solid. This solid wascombined with SnCl₂ (7.0 g, 31 mmol), glacial acetic acid (35 mL) andHCl (35 mL of 12 N) and heated to 100° C. for 1 hour. The resultingsolution was cooled to room temperature, poured into water (100 mL), andextracted with ethyl acetate (3×200 mL). The combined organic layerswere washed with water, dried over sodium sulfate, filtered, stripped ofsolvent, and purified on silica 2.5% ethyl acetate—hexanes) to yield1.97 g (41%) of the title compound as a white solid: mp 124-126° C.; ¹HNMR (DMSO-d₆): δ 7.20 (1H, s), 7.23 (1H, d, J=2.39 Hz), 7.48 (1H, dd,J=1.78 Hz, J=10.52 Hz), 7.84-7.88 (1H, m), 7.94 (1H, d, J=0.79 Hz),10.28 (1H, s); MS (ESI) m/z 239/241 (M−H)⁻.

[0341] Anal. for C₁₀H₆BrFO: Calc'd: C: 49.83H: 2.51 Found: C: 49.86H:2.46

Intermediate 69 3,6-Dibromo-8-chloro-2-naphthol

[0342] To a solution of 8-chloro-2-naphthol (4.92 g, 27.6 mmol) inglacial acetic acid (40 mL) was slowly added a solution of bromine (9.7g, 60.7 mmol) in glacial acetic acid (40 mL). The solution was stirredat 100° C. for 1 hour, cooled to room temperature, poured into water(250 mL), and extracted with ethyl acetate. The combined organic layerswere washed with sodium bicarbonate, dried with sodium sulfate,filtered, stripped of solvent, and purified on a silica column (20%ethyl acetate—hexanes) to yield 4.61 g (50%) of a yellow solid. Ananalytical sample was further purified by reverse phase preparative HPLCto yield the title compound as a white solid: mp 156-158° C.; ¹H NMR(DMSO-d₆): δ 7.57 (1H, s), 7.82 (1H, d, J=1.89 Hz), 8.11 (1H, d, J=1.69Hz), 8.31 (1H, s), 11.30 (1H, bs); MS (ESI) m/z333/335/337 (M−H)⁻.

[0343] Anal. for C₁₀H₅Br₂ClO: Calc'd: C: 35.70H: 1.50 Found: C: 35.74H:1.44

Intermediate 70 3-Bromo-7-hydroxy-1-naphthonitrile

[0344] To a mixture of 7-hydroxy-1-naphthonitrile (26.03 g, 154.0 mmol)and glacial acetic acid (400 mL) was added bromine (51.8 g, 323 mmol).The mixture was stirred at 100° C. for 6 hr. HCl (400 mL of 12 Nsolution) and SnCl₂ (69 g, 308 mmol) were added and the mixture wasstirred at 100° C. for 1 hour. The resulting solution was cooled to roomtemperature and poured into water (1 l). The resulting yellowprecipitate was collected by filtration, dried under vacuum, andtriturated with ethyl acetate to yield 14.68 g (38%) of the titlecompound as an off-white solid. An analytical sample was prepared bypreparative reverse phase HPLC to yield the title compound as a whitesolid: mp 222-224° C.; ¹H NMR (DMSO-d₆): δ 7.28-7.35 (2H, m), 7.97 (1H,d, J=8.73 Hz), 8.26 (1H, s), 8.47 (1H, s), 10.65 (1H, s); MS (ESI)m/z246/247 (M−H)⁻.

[0345] Anal. for C₁₁H₆BrNO: Calc'd: C: 53.26H: 2.44 N: 5.65 Found: C:52.81H: 2.70 N: 4.82.

Intermediate 71tert-Butyl[(3,6-dibromo-8-chloro-2-naphthyl)oxy]dimethylsilane

[0346] The title compound was prepared by reacting3,6-dibromo-8-chloro-2-naphthol (3.00 g, 8.92 mmol) with TBDMS-Cl (1.75g, 150.7 mmol) according to method F to yield 3.36 g (84%) of a whitesolid: mp 58-64° C.; ¹H NMR (CDCl₃): δ 0.34 (6H, s), 1.08 (9H, s), 7.57(1H, s), 7.62 (1H, d, J=1.72 Hz), 7.75 (1H, d, J=1.24 Hz), 7.97 (1H, s);MS (ESI) m/z333/335/337 (M−H)⁻.

[0347] Anal. for C₁₆H₁₉Br₂ClOSi: Calc'd: C: 42.64H: 4.25 Found: C:42.73H: 4.08

Intermediate 72 8-Fluoro-6-(4-methoxyphenyl)-2-naphthol

[0348] The title compound was prepared by reacting6-bromo-8-fluoro-2-naphthol (0.39 g, 1.62 mmol) with 4-methoxyphenylboronic acid (0.34 g, 2.27 mmol) according to method A to yield 0.35 g(81%) of a white solid: mp 150-151° C.; ¹H NMR (DMSO-d₆): δ 3.81 (3H,s), 7.05 (2H, d, J=8.75 Hz), 7.16-7.20,(2H, m), 7.57 (1H, dd, J=1.21 Hz,J=12.76 Hz), 7.74 (2H, d, J=8.74 Hz), 7.89-7.92 (2H, m), 10.10 (1H, s);MS (ESI) m/z269 (M−H)⁺.

[0349] Anal. for C₁₇H₁₃FO₂.0.1H₂O: Calc'd: C: 75.60H: 4.93 Found: C:75.30H: 4.57

Intermediate 73 8-Fluoro-6-(3-fluoro-4-methoxyphenyl)-2-naphthol

[0350] The title compound was prepared by reacting6-bromo-8-fluoro-2-naphthol (0.66 g, 2.74 mmol) with3-fluoro-4-methoxyphenyl boronic acid (0.56 g, 3.3 mmol) according tomethod A to yield 0.67 g (85%) of a white solid: mp 138-140° C.; ¹H NMR(DMSO-d₆): δ 3.90 (3H, s), 7.17-7.30 (3H, m), 7.60-7.65 (2H, m), 7.71(1H, dd, J=2.19 Hz), J=13.14 Hz), 7.90 (1H, d, J=8.37 Hz), 7.99 (1H,bs), 10.15 (1H, bs); MS (ESI) m/z285 (M−H)⁻.

[0351] Anal. for C₁₇H₁₂F₂O₂: Calc'd: C: 71.32H: 4.23 Found: C: 71.09H:4.15

Intermediate 74tert-Butyl[(3-bromo-8-chloro-(4-methoxyphenyl)-2-naphthyl)oxy]dimethylsilane

[0352] A solution oftert-butyl[(3,6-dibromo-8-chloro-2-naphthyl)oxy]dimethylsilane (1.95 g,4.32 mmol), 4-methoxyphenylmagnesium bromide (13.8 mL of 0.5 N solution,6.9 mmol), and tetrakis(triphenylphosphine)palladium (0.25 g, 0.21 mmol)in THF (10 mL) were stirred at reflux for 8 hr. The reaction wasquenched with water (100 mL) and extracted with ethyl acetate (3×150mL). The combined organic layers were washed with water, dried withsodium sulfate, filtered, evaporation of the solvent, and purified on asilica column (5% ethyl acetate—hexanes) to yield 1.42 g (69%) of thetitle compound as a white solid: ¹H NMR (CDCl₃): δ 0.36 (6H, s), 1.10(9H, s), 3.87 (3H, s), 7.01 (2H, d, J=8.78 Hz), 7.33(1H,d, J=1.36 Hz),7.58 (2H, d, J=8.75 Hz), 7.73 (1H, s), 7.78 (1H, d, J=1.62 Hz), 8.10(1H, s).

Intermediate 75 7-Hydroxy-3-(4-methoxyphenyl)-1-naphthonitrile

[0353] The title compound was prepared by. reacting3-bromo-7-hydroxy-1-naphthonitrile (0.249 g, 1.00 mmol) with4-methoxyphenylboronic acid (0.21 g, 1.4 mmol) according to Method A toyield 0.19 (69%) of a light yellow solid: mp 226° C.; ¹H NMR (DMSO-d₆):δ 3.82 (3H, s), 7.07 (2H, d, J=8.82 Hz), 7.26 (1H, dd, J=2.32 Hz, J=8.90Hz), 7.37 (1H, d, J=2.27 Hz), 7.80 (2H, d, J=8.80 Hz), 8.02 (1H, d,J=8.96 Hz), 8.37 (1H, d, J=1.85 Hz), 8.44 (1H, d, J=1.43 Hz), 10.48 (1H,bs); MS (ESI) m/z 274 (M−H)⁻.

[0354] Anal. for C₁₈H₁₃NO₂ 0.1H₂O: Calc'd: C: 78.02H: 4.80 N: 5.05Found: C: 77.73H: 4.65 N: 4.92.

Intermediate 76 3-(3-Fluoro-4-methoxyphenyl)-7-hydroxy-1-naphthonitrile

[0355] The title compound was prepared by reacting3-bromo-7-hydroxy-1-naphthonitrile (0.208 g, 0.839 mmol) with3-fluoro-4-methoxyphenylboronic acid (0.18 g, 1.1 mmol) according tomethod A to yield 0.16 (65%) of a light yellow solid. An analyticalsample was prepared by preparative reverse phase HPLC to yield the titlecompound as a white solid: mp 214-216° C.; ¹H NMR (DMSO-d₆): δ 3.90 (3H,s), 7.23-7.32 (2H, m), 7.37 (1H, d, J=2.24 Hz), 7.65-7.70 (1H, m), 7.79(1H, dd, J=2.22 Hz, J=13.10 Hz), 8.03 (1H, d, J=8.96 Hz), 8.41 (1H, d,J=1.86 Hz), 8.50 (1H, d, J=1.43 Hz), 10.55 (1H, s); MS (ESI) m/z292(M−H)⁻.

[0356] Anal. for C₁₈H₁₂FNO₂ 0.1H₂O: Calc'd:C: 73.26H: 4.17 N: 4.75Found: C: 72.91H: 4.01 N: 4.60.

Intermediate 77 3-Bromo-8-chloro-6-(4-methoxyphenyl)-2-naphthol

[0357] Method I

[0358] To a solution oftert-butyl[(3-bromo-8-chloro-(4-methoxyphenyl)-2-naphthyl)oxy]dimethylsilane(0.50 g, 1.06 mmol) in THF (20 mL) was added TBAF (5 mL of 1N solutionin THF, 55 mmol). The solution was stirred for one hour at roomtemperature, evaporation of the solvent, taken up in water (50 mL), andextracted with ethyl acetate (3×150 mL). The combined organic layerswere washed with water, dried with sodium sulfate, filtered, stripped ofsolvent, and purified on a silica column (10% ethyl acetate—hexanes) toyield 0.34 g (88%) of a white solid. An analytical sample was furtherprepared by reverse phase preparative HPLC to yield the title compoundas a white solid: mp 138-139° C.; ¹H NMR (DMSO-d₆): δ 3.82 (3H, s), 7.06(2H, d, J=8.76 Hz), 7.58 91H, s), 7.73 (2H, d, J=8.73 Hz), 7.94 (1H, d,J=1.56 Hz), 8.07 (H, bs), 8.34 (1H, s), 11.05 (1H, s); MS (ESI)m/z361/363/365 (M−H)⁻.

[0359] Anal. for C₁₇H₁₂BrClO₂ 0.6H₂O: Calc'd:C: 54.53H: 3.55 Found: C:54.30H: 3.11

EXAMPLE 1az 3-(3,5-Difluoro-4-hydroxyphenyl)-7-hydroxy-1-naphthonitrile

[0360] The title compound was prepared by reacting3-bromo-7-hydroxy-1-naphthonitrile (0.124 g, 0.50 mmol) with2,5-difluoro-4-tert-butyldimethylsilyloxyphenylboronic acid (0.17 g,0.59 mmol) according to method A to yield 0.090 g (61%) of a yellowsolid. An analytical sample was prepared by preparative reverse phaseHPLC to yield the title compound as a light yellow solid: mp 300-304°C.(d); ¹H NMR (DMSO-d₆): δ 7.27 91H, dd, J=2.26 Hz, J=8.88 Hz), 7.36(1H, d, J=2.12 Hz), 7.63-7.66 (2H, m), 8.00 (1H, d, J=8.95 Hz), 8.43(1H, d, J=1.77 Hz), 8.52 (1H, s), 10.44 (1H, s), 10.54 (1H, s); MS (ESI)m/z296 (M−H)⁻.

[0361] Anal. for C₁₇H₉F₂NO₂ 0.3H₂O: Calc'd:C: 67.46H: 3.20 N: 4.63Found: C: 67.18H: 2.89 N: 4.55.

EXAMPLE 1aj 8-Fluoro-6-(4-hydroxyphenyl)-2-naphthol

[0362] The title compound was prepared by reacting8-fluoro-6-(4-methoxyphenyl)-2-naphthol (0.10 g, 0.37 mmol) with borontribromide (0.56 mL of 1N solution, 0.56 mmol) according to method D toyield 0.10 g (quantitative) of a white solid: mp 236-238° C.; ¹H NMR(DMSO-d₆): δ 6.87 (2H, d, J=8.57 Hz), 7.14-7.18 (2H, m), 7.52 (1H, dd,J=1.18 Hz, J=12.78 Hz), 7.61 (2H, d, J=8.59 Hz, 7.86-7.89 (2H, m), 9.61(1H, bs), 10.05 (1H, bs); MS (ESI) m/z253 (M−H)⁻.

[0363] Anal. for C₁₆H₁₁FO₂ 0.1H₂O: Calc'd: C: 75.06H: 4.41 Found: C:75.01H: 4.11

EXAMPLE 1ak 8-Fluoro-6-(3-fluoro-4-hydroxyphenyl)-2-naphthol

[0364] The title compound was prepared by reacting8-fluoro-6-(3-fluoro-4-methoxyphenyl)-2-naphthol (0.10 g, 0.35 mmol)with boron tribromide (0.7 mL of 1N solution, 0.7 mmol) according tomethod D to yield 0.020 g (21%) of a white solid: mp 218-220° C. d; ¹HNMR (DMSO-d₆): δ 7.01-7.07 (1H, m), 7.16-7.19 (2H, m), 7.46 (1H, dd,J=1.74 Hz, J=8.40 Hz), 7.56-7.65 (2H, m), 7.88 (1H, d, J=8.31 Hz), 7.93(1H, bs), 10.04 (1H, s), 10.11 (1H, s); MS (ESI) m/z 271 (M−H)⁻.

[0365] Anal. for C₁₆H₁₀F₂O₂ 0.25H₂O Calc'd: C: 69.44H: 3.82 Found: C:69.13H: 3.45

EXAMPLE 1au 7-Hydroxy-3-(4-hydroxyphenyl)-1-naphthonitrile

[0366] The title compound was prepared by reacting7-hydroxy-3-(4-methoxyphenyl)-1-naphthonitrile (0.14 g, 0.51 mmol) withpyridinium HCl (3 g) according to method B to yield 0.10 g (75%) of awhite solid: mp 254-257° C.; ¹H NMR (DMSO-d₆): δ 6.89 (2H, d, J=8.53Hz), 7.25 (1H, dd, J=2.15 Hz, J=8.88 Hz), 7.36 (1H, d, J=1.86 Hz), 7.67(2H, d, J=8.55 Hz), 8.00 (1H, d, J=8.94 Hz), 8.31-8.38 (2H, m), 9.70(1H, bs), 10.44 (1H, bs); MS (ESI) m/z260 (M−H)⁻.

[0367] Anal. for C₁₇H₁₁NO₂ 0.25H₂O Calc'd:C: 76.83H: 4.36 N: 5.27 Found:C: 76.85H: 4.31 N: 5.10.

EXAMPLE 1av 3-(3-Fluoro-4-hydroxyphenyl)-7-hydroxy-1-naphthonitrile

[0368] The title compound was prepared by reacting7-hydroxy-3-(3-fluoro-4-methoxyphenyl)-1-naphthonitrile (0.12 g, 0.41mmol) with pyridinium HCl (3 g) according to method B to yield 0.085 g(74%) of a white solid: mp 265-269° C.; ¹H NMR (DMSO-d₆): δ 7.04-7.09(1H, m), 7.26 (1H, dd, J=2.31 Hz, J=8.88 Hz), 7.36 (1H, d, J=2.19 Hz),6.52 (1H, d, J=2.19 Hz), 6.52 (1H, dd, J=1.76 Hz, J=8.40 Hz), 6.71 (1H,dd, J=2.22 Hz, J=12.88 Hz), 8.01 (1H, d, J=8.97 Hz), 8.37 (1H, d, J=1.83Hz), 8.45 (1H, d, J=1.41 Hz), 10.33 (2H, bs); MS (ESI) m/z278 (M−H)⁻.

[0369] Anal. for C₁₇H₁₀FNO₂: Calc'd: C: 73.11H: 3.61 N: 5.02 Found: C:72.75H: 3.45 N: 4.82.

[0370] Synthesis of Compounds in Scheme 13

Intermediate 78 and Intermediate 79 1-Chloro-6-methoxy-2-naphthol and1,5-Dichloro-6-methoxy-2-naphthol

[0371] A mixture of 6-methoxy-2-naphthol (5.43 g, 31.17 mmol), NCS (4.58g, 34.3 mmol), and acetonitrile (150 mL) was stirred overnight at roomtemperature according to Method A. The solvent was removed and theresulting brown solid residue was taken up in ethyl acetate (500 mL),washed with water, dried over sodium sulfate, evaporation of solvent,and purification on a silica column (20% ethyl acetate—hexanes) yieldeda white solid. This solid was further purified by reverse phasepreparative HPLC to yield 3.91 g (60%) of intermediate 78 as a whitesolid: mp 104-105° C.; ¹H NMR (DMSO-d₆): δ 3.85 (3H, s), 7.22-7.26 (2H,m), 7.31 (1H, d, J=2.42 Hz), 7.68 (1H, d, J=8.91 Hz), 7.93 (1H, d,J=9.17 Hz); MS (ESI) m/z207/209 (M−H)⁻.

[0372] Anal. for C₁₁H₉ClO₂: Calc'd: C: 63.32H: 4.35 Found: C: 63.21H:4.50

[0373] The HPLC separation also yielded 0.83 g (3.43 mmol) ofintermediate 79 as a white solid: mp 152-158° C.; ¹H NMR (DMSO-d₆): δ3.97 (3H, s), 7.41 (1H, d, J=9.22 Hz), 7.63 (1H, d, J=9.17 Hz), 7.97(1H, d, J=9.23 Hz), 8.04 (1H, d, J=9.34 Hz), 10.51 (1H, s); MS (ESI)m/z241/243 (M−H)⁻.

[0374] Anal. for C₁₁H₈Cl₂O₂: Calc'd: C: 54.35H: 3.32 Found: C: 54.13H:3.21

Intermediate 80 1-Chloro-6-methoxy-2-naphthyl trifluoromethanesulfonate

[0375] The title compound was prepared by reacting1-chloro-6-methoxy-2-naphthol (0.70 g, 3.36 mmol) withtrifluoromethanesulfonic anhydride (1.23 g, 4.4 mmol) according tointermediate 6 to yield 1.02 g (89%) of a white solid: mp 60-61° C.; ¹HNMR (CDCl₃): δ 3.95 (3H, s), 7.17 (1H, d, J=2.48 Hz), 7.35 (1H, dd,J=2.50 Hz, J=9.30 Hz), 7.39 (1H, d, J=9.06 Hz), 7.71 (1H, d, J=9.11 Hz),8.21 (1H, d, J=9.28 Hz); MS (EI) m/z 340/342 (M)⁺.

[0376] Anal. for C₁₂H₈ClF₃O₄S Calc'd:C: 42.30H: 2.37 Found: C: 42.20H:2.37

Intermediate 81 1,5-Dichloro-6-methoxy-2-naphthyltrifluoromethanesulfonate

[0377] The title compound was prepared by reacting1,5-dichloro-6-methoxy-2-naphthol (0.27 g, 1.11 mmol) withtrifluoromethanesulfonic anhydride (0.41 g, 1.44 mmol) according tointermediate 6 to yield 0.37 g (89%) of a white solid: mp 73-78° C.; ¹HNMR (CDCl₃): δ 4.08 (3H, s), 7.48-7.52 (2H, m), 8.24-8.30 (2H, m); MS(EI) m/z 374/376/378 (M)+.

[0378] Anal. for C₁₂H₇Cl₂F₃O₄S: Calc'd: C: 38.42H: 1.88 Found: C:38.65H: 1.90

Intermediate 82 1-Chloro-6-methoxy-2-(4-methoxyphenyl)naphthalene

[0379] The title compound was prepared by reacting1-chloro-6-methoxy-2-naphthyl trifluoromethanesulfonate (0.95 g, 2.79mmol) with 4-methoxyphenyl boronic acid (0.59 g, 3.9 mmol) according tomethod A to yield 0.71 g (85%) of a white solid: mp 126-128° C.; ¹H NMR(CDCl₃): δ 3.88 (3H, s), 3.95 (3H, s), 7.01 (2H, d, J=8.60 Hz), 7.16(1H, d, J=2.49 Hz), 7.27 (1H, dd, J=1.97 Hz, J=8.99 Hz), 7.41 (1H, d,J=8.45 Hz), 7.46 (2H, d, J=8.61 Hz), 7.68 (1H, d, J=8.48 Hz), 8.28 (1H,d, J=9.27 Hz); MS (ESI) m/z 299/301 (M+H)⁺.

[0380] Anal. for C₁₈H₁₅ClO₂ 0.25H₂O Calc'd: C: 71.29H: 5.15 Found: C:70.84H: 4.80

Intermediate 83 1,5-Dichloro-2-methoxy-6-(4-methoxyphenyl)naphthalene

[0381] The title compound was prepared by1,5-dichloro-6-methoxy-2-naphthyl trifluoromethanesulfonate (0.32 g,0.85 mmol) with 4-methoxyphenyl boronic acid (0.18 g, 1.2 mmol)according to method A to yield 0.27 g (95%) of a white solid mp 146-149°C.;¹H NMR (CDCl₃): δ 3.88 (3H, s), 4.07 (3H, s), 7.02 (2H, d, J=8.73Hz), 7.41 (1H, d, J=9.52 Hz), 7.46 (2H, d, J=8.83 Hz), 7.53 (1H, d,J=8.73 Hz), 8.19 (1H, d, J=8.73 Hz), 8.36 (1H, d, J=9.12 Hz);

[0382] Anal. for C₁₈H₁₄Cl₂O₂: Cald'd: C: 64.88H: 4.23 Found: C: 64.63H:4.28

EXAMPLE 1ao 5-Chloro-6-(4-hydroxyphenyl)-2-naphthol

[0383] The title compound was prepared by reacting1-chloro-6-methoxy-2-(4-methoxyphenyl)naphthalene (0.65 g, 2.18 mmol)with boron tribromide (6.5 mL of 1N solution) according to method D toyield 0.44 g (75%) of a white solid: mp>220° C.;

[0384]¹H NMR (DMSO-d₆): δ 6.86 (2H, d, J=8.33 Hz), 7.23-7.28 (2H, m),7.30 (2H, d, J=8.32 Hz), 7.37 (1H, d, J=8.51 Hz), 7.72 (1H, d, J=8.55Hz), 8.13 (1H, d, J=9.07 Hz); MS (ESI) m/z269/271(M−H)⁻.

[0385] Anal. for C₁₆H₁₁ClO₂ 0.1H₂O Calc'd: C: 70.52H: 4.14 Found: C:70.52H: 4.05

EXAMPLE 1ap 1,5-Dichloro-6-(4-hydroxyphenyl)-2-naphthol

[0386] The title compound was prepared by reacting1,5-dichloro-2-methoxy-6-(4-methoxyphenyl)naphthalene (0.15 g, 0.45mmol) with boron tribromide (1.4 mL of 1N solution) according to methodD to yield 0.10 g (73%) of a white solid: mp 204-206° C.;

[0387]¹H NMR (DMSO-d₆): δ 6.89 (2H, d, J=8.47 Hz), 7.33 (2H, d, J=8.45Hz), 7.46 (1H, d, J=9.26 Hz), 7.56 (1H, d, J=8.80 Hz), 8.06 (1H, d,J=8.81 Hz), 8.17 (1H, d, J=9.28 Hz), 9.68 (1H, bs), 10.84 (1H, bs); MS(ESI) m/z303/305/307(M−H)⁻.

[0388] Anal. for C₁₆H₁₀Cl₂O₂ Calc'd: C: 62.98H: 3.30 Found: C: 62.78H:3.28

[0389] Synthesis of Compounds in Scheme 14

Intermediate 84 8-Chloro-6-(4-methoxyphenyl)-2-naphthol

[0390] To a solution of 3-bromo-8-chloro-6-(4-methoxyphenyl)-2-naphthol(0.254 g, 0.698 mmol) in THF (25 mL) at −78° C. was slowly added t-butyllithium (1.65 mL of 1.7N solution, 2.8 mmol). The resulting solution wasstirred for twenty minutes at −78° C. and 2.5 mL of water was added andthe mixture was warmed to room temperature slowly with stirring. Thereaction was poured into 50 mL of water and extracted with ethyl acetate(3×100 mL). The combined organic layers were washed with water, driedwith sodium sulfate, filtered, evaporated off the of solvent, andpurified on a silica column (10% ethyl acetate—hexanes) to yield 0.15 g(88%) of a yellow solid. An analytical sample was further prepared byreverse phase preparative HPLC to yield the title compound as a lightyellow solid: mp 116-118° C.; ¹H NMR (DMSO-d₆): δ 3.81 (3H, s), 7.05(2H, d, J=8.75 Hz), 7.19 (1H, dd, J=2.34 Hz, J=8.84 Hz), 7.40 (1H, d,J=2.25 Hz), 7.74 (2H, d, J=8.73 Hz), 7.89 (1H, d, J=1.65 Hz), 7.92 (1H,d, J=8.93 Hz), 8.07 (1H, s), 10.19 (1H, s); MS (ESI) m/z283/285 (M−H)⁻.

[0391] Anal. for C₁₇H₁₃ClO₂ 0.1H₂O: Calc'd: C: 71.26H 4.64 Found: C:71.18H: 4.43 N

Intermediate 851-Chloro-8-fluoro-6-(3-fluoro-4-methoxyphenyl)-2-naphthol

[0392] The title compound was prepared by reacting8-fluoro-6-(3-fluoro-4-methoxyphenyl)-2-naphthol (0.30 g, 1.05 mmol) andNCS (0.17 g, 1.26 mmol) according to method C to yield 0.21 g (62%) of alight orange solid: mp 126-128° C.; ¹H NMR (DMSO-d₆): δ 3.90 (3H, s),7.25-7.31 (1H, m), 7.35 (1H, d, J=8.91 Hz), 7.64-7.67 (1H, m), 7.70-7.78(2H, m), 7.87 (1H, dd, J=1.58 Hz, J=9.04 Hz), 10.68 (1H, s); MS (ESI)m/z3191321 (M−H)⁻.

[0393] Anal. for C₁₇H₁₁ClF₂O₂: Calc'd: C: 63.66H: 3.46 Found: C: 63.23H:3.39

Intermediate 86 1-Chloro-8-fluoro-6-(4-methoxyphenyl)-2-naphthol

[0394] A solution of 8-fluoro-6-(4-methoxyphenyl)-2-naphthol (0.17 g,0.63 mmol) and NCS (0.10 g, 0.76 mmol) in THF (20 mL) were stirred undernitrogen at room temperature overnight according to Method C. Thesolution was concentrated onto Florosil and purified on a silica column(20% ethyl acetate—hexanes) to yield 0.16 g (84%) of the title compoundas a yellow solid. An analytical sample was further prepared bypreparative reverse phase HPLC to yield a light yellow solid: mp120-124° C.; ¹H NMR (DMSO-d₆): δ 3.82 (3H, s), 7.06 (2H, d, J=8.80 Hz),7.34 (1H, d, J=8.91 Hz), 7.67 (1H, dd, J=1.69 Hz, J=15.48 Hz), 7.78 (2H,d, J=8.78 Hz), 8.01 (1H, d, J=1.54 Hz), 10.62 (1H, s); MS (ESI) m/z301/303 (M−H)⁻.

[0395] Anal. for C₁₇H₁₂ClFO₂ Calc'd: C: 67.45H: 4.00 Found: C: 67.23H:3.65

Intermediate 87 1,5-Dichloro-8-fluoro-6-(4-methoxyphenyl)-2-naphthol

[0396] The title compound was prepared by reacting8-fluoro-6-(4-methoxyphenyl)-2-naphthol (0.24 g, 0.90 mmol) and NCS(0.22 g, 1.6 mmol) in acetonitrile (20 mL) according to method C toyield 0.22 g (73%) of a yellow solid: ¹H NMR (DMSO-d₆): δ 3.82 (3H, s),7.06 (2H, d, J=8.69 Hz), 7.39 (1H, d, J=14.34 Hz), 7.47 (2H, d, J=8.68Hz), 7.53 (1H, d, J=9.36 Hz), 8.22 (1H, dd, J=1.65 Hz, J=9.32 Hz), 11.01(1H, s); MS (ESI) m/z3351337 (M−H)⁻.

Intermediate 88 3-Bromo-1,8-dichloro-6-(4-methoxyphenyl)-2-naphthol

[0397] The title compound was prepared by reacting3-bromo-8-chloro-6-(4-methoxyphenyl)-2-naphthol (0.69 g, 1.90 mmol) andNCS (0.31 g, 2.3 mmol) in THF (25 mL) according to method C to yield0.61 g (81%) of a yellow solid. An analytical sample was furtherprepared by reverse phase preparative HPLC to yield the title compoundas a white solid: mp 176-178° C. (dec.); ¹H NMR (DMSO-d₆): δ 3.82 (3H,s), 7.08 (2H, d, J=8.77 Hz), 7.77 (2H, d, J=8.75 Hz), 8.00 (1H, d,J=1.84 Hz), 8.19 (1H, d, J=1.84 Hz), 8.39 (1H, s), 10.53 (1H, bs); MS(ESI) m/z39513971399 (M−H)⁻.

[0398] Anal. for C₁₇H₁₁BrCl₂O₂ Calc'd:C: 51.29H: 2.79 Found: C: 51.37H:2.62

Intermediate 89 8-Bromo-7-hydroxy-3-(4-methoxyphenyl)-1-naphthonitrile

[0399] The title compound was prepared by reacting7-hydroxy-3-(4-methoxyphenyl)-1-naphthonitrile (0.160 g, 0.58 mmol) withNBS (0.12 g, 0.70 mmol) in THF (10 mL) according to method C to yield0.080 g (39%) of a yellow solid: mp 145-146° C.; ¹H NMR (DMSO-d₆): δ3.83 (3H, s), 7.08 (2H, d, J=8.79 Hz), 7.42 (1H, d, J=8.79 Hz), 7.84(2H, d, J=8.79 Hz), 8.04 (1H, d, J=8.79 Hz), 8.42 (1H, d, J=1.95 Hz),8.53 (1H, d, J=1.95 Hz), 11.21 (1H, s); MS (ESI) m/z 354/356 (M+H+; MS(ESI) m/z 352/354 (M−H)⁻.

[0400] Anal. for C₁₈H₁₂BrNO₂ 0.25H₂O Calc'd: C: 60.27H: 3.51 N: 3.90Found: C: 60.27H: 3.51 N: 3.46.

Intermediate 90 1,8-Dichloro-6-(4-methoxyphenyl)-2-naphthol

[0401] The title compound was prepared by reacting3-bromo-1,8-dichloro-6-(4-methoxyphenyl)-2-naphthol (0.30 g, 0.754 mmol)with t-butyl lithium (1.75 mL of 1.7N solution, 3.0 mmol) and quenchingwith water according to the method use to prepare intermediate 84 toyield 0.19 g (79%) of a yellow solid. An analytical sample was furtherprepared by reverse phase preparative HPLC to yield the title compoundas a light yellow solid: mp 132-134° C.; ¹H NMR (DMSO-d₆): δ 3.82 (3H,s), 7.06 (2H, d, J=8.77 Hz), 7.37 (1H, d, J=8.90 Hz), 7.77 (2H, d,J=8.75 Hz), 7.89-7.93 (2H, m), 8.15 (1H, d, J=1.85 Hz), 10.68 (1H, s);MS (ESI) m/z 317/319/321 (M−H)⁻.

[0402] Anal. for C₁₇H₁₂Cl₂O₂ Calc'd: C: 63.97H: 3.79 Found: C: 63.57H:3.65

EXAMPLE 1al 1-Chloro-8-fluoro-6-(4-hydroxyphenyl)-2-naphthol

[0403] The title compound was prepared by reacting1-chloro-8-fluoro-6-(4-methoxyphenyl)-2-naphthol (0.14 g, 0.46 mmol)with boron tribromide (0.69 mL of 1N solution, 0.69 mmol) according tomethod D to yield 0.050 g (38%) of a white solid mp 174-176° C.; ¹H NMR(DMSO-d₆): δ 6.88 (2H, d, J=8.62 Hz), 7.33 (1H, d, J=8.92 Hz), 7.60-7.67(3H, m), 7.86 (1H, dd, J=1.43 Hz, J=9.02 Hz), 7.95 (1H, d, J=1.37 Hz),9.68 (1H, s), 10.59 (1H, s); MS (ESI) m/z 287/289 (M−H)⁻.

[0404] Anal.for C₁₆H₁₀ClFO₂ 0.25H₂O Calc'd:C: 65.54H: 3.61 Found: C:65.52H: 3.19

EXAMPLE 1am 1-Chloro-8-fluoro-6-(3-fluoro-4-hydroxyphenyl)-2-naphthol

[0405] The title compound was prepared by reacting1-chloro-8-fluoro-6-(3-fluoro-4-methoxyphenyl)-2-naphthol (0.13 g, 0.41mmol) with boron tribromide (0.8 mL of 1N solution, 0.8 mmol) accordingto method D to yield 0.070 g (56%) of a white solid mp 198-200° C.; ¹HNMR (DMSO-d₆): δ 7.03-7.09 (1H, m) 7.34 (1H, d, J=8.92 Hz), 7.49-7.52(1H, m), 7.68 (2H, d, J=15.0 Hz), 7.85-7.88 (1H, m), 8.02 (1H, d, J=0.70Hz), 10.13 (1H, s), 10.66 (1H, s); MS (ESI) m/z 305/307 (M−H)⁻.

[0406] Anal. for C₁₆H₉ClF₂O₂ Calc'd: C: 62.66H: 2.96 Found: C: 62.27H:2.90

EXAMPLE 1an 8-Chloro-6-(4-hydroxyphenyl)-2-naphthol

[0407] The title compound was prepared by reacting8-chloro-6-(4-methoxyphenyl)-2-naphthol (0.10 g, 0.35 mmol) with borontribromide (0.9 mL of 1N solution, 0.9 mmol) according to method D toyield 0.080 g (85%) of product which was further purified by reversephase preparative HPLC to yield the title compound as a white solid: mp204-206° C.; ¹H NMR (DMSO-d₆): δ 6.87 (2H, d, J=8.61 Hz), 7.17 (1H, dd,J=2.34 Hz, J=8.83 Hz), 7.38 (1H, d, J=2.26 Hz), 7.62 (2H, d, J=8.59 Hz),7.85 (1H, d, J=1.64 Hz), 7.90 (1H, d, J=8.92 Hz), 8.01 (1H, bs), 9.62(1H, s), 10.14 (1H, s); MS (ESI) m/z 269/(M−H)⁻.

[0408] Anal. for C₁₆H₁₁ClO₂ 0.25H₂O Calc'd: C: 70.99H: 4.10 Found: C:69.95H: 3.89

EXAMPLE 1aq 1,5-Dichloro-8-fluoro-6-(4-hydroxyphenyl)-2-naphthol

[0409] The title compound was prepared by reacting1,5-dichloro-8-fluoro-6-(4-methoxyphenyl)-2-naphthol (0.15 g, 0.445mmol) with boron tribromide (0.67 mL of 1 N solution, 0.67 mmol)according to method D to yield 0.12 g (83%) of a light yellow solid mp206-216° C.; ¹H NMR (DMSO-d₆): δ 6.88 (2H, d, J=8.55 Hz), 7.34-7.39 (3H,m), 7.51 (1H, d, J=9.34 Hz), 8.21 (1H, dd, J=1.66 Hz, J=9.34 Hz), 9.74(1H, bs), 10.99 (1H, bs); MS (ESI) m/z321/323/326 (M−H)⁻.

[0410] Anal. for C₁₆H₉Cl₂FO₂ 0.1H₂O Calc'd: C: 59.13H: 2.85 Found: C:58.88H: 2.85

EXAMPLE 1ar 3-Bromo-8-chloro-6-(4-hydroxyphenyl)-2-naphthol

[0411] The title compound was prepared by reacting3-bromo-8-chloro-6-(4-methoxyphenyl)-2-naphthol (0.24 g, 0.66 mmol) withboron tribromide (1.6 mL of 1N solution, 1.6 mmol) according to method Dto yield 0.14 g (61%) of a yellow oil. The product was further purifiedby reverse phase preparative HPLC to yield the title compound as a whitesolid: mp 188-190° C.; ¹H NMR (DMSO-d₆): δ 6.88 (1H, d, J=8.60 Hz), 7.57(1H, s), 7.71 (2H, d, J=8.61 Hz), 7.89 (1H, d, J=1.60 Hz), 8.02 (1H, s),8.31 (1H, s), 9.67 (1H, s), 11.01 (1H, s); MS (ESI) m/z 347/349/351(M−H)⁻.

[0412] Anal. for C₁₆H₁₀BrClO₂: Calc'd: C: 54.97H: 2.88 Found: C: 54.68H:2.82

EXAMPLE 1as 1,8-Dichloro-6-(4-hydroxyphenyl)-2-naphthol

[0413] The title compound was prepared by reacting1,8-dichloro-6-(4-methoxyphenyl)-2-naphthol (0.12 g, 0.38 mmol) withboron tribromide (0.75 mL of 1N solution, 0.75 mmol) according to methodD to yield 0.10 (86%) of which was further purified by reverse phasepreparative HPLC to yield the title compound as a white solid: mp172-174° C. (dec.); ¹H NMR (DMSO-d₆): δ 6.89 (2H, d, J=8.54 Hz), 7.36(1H, d, J=8.90 Hz), 7.65 (2H, d, J=8.56 Hz), 7.88-7.91 (2H, m), 8.10(1H, d, J=1.63 Hz), 9.69 (1H, s), 10.64 (1H, s); MS (ESI) m/z303/305/307(M−H)⁻.Anal. for C₁₆H₁₀Cl₂O₂ 0.25H₂O Calc'd: C: 62.98H: 3.30 Found: C:61.80H: 3.08

EXAMPLE 1at 3-Bromo-1,8-dichloro-6-(4-hydroxyphenyl)-2-naphthol

[0414] The title compound was prepared by reacting3-bromo-1,8-dichloro-6-(4-methoxyphenyl)-2-naphthol (0.18 g, 0.45 mmol)with boron tribromide (0.9 mL of 1N solution, 0.9 mmol) according tomethod D to yield 0.12 g (69%) of a light brown solid. The product wasfurther purified by reverse phase preparative HPLC to yield the titlecompound as a white solid: mp 184-188° C.; ¹H NMR (DMSO-d₆): δ 6.89 (2H,d, J=8.59 Hz), 7.65 (2H, d, J=8.61 Hz), 7.95 (1H, d, J=1.78 Hz), 8.13(1H, d, J=1.75 Hz), 8.37 (1H, s), 9.74 (1H, s), 10.50 (1H, s); MS (ESI)m/z 381/383/385 (M−H)⁻.

[0415] Anal. for C₁₆H₉BrCl₂O₂ 0.25H₂O Calc'd: C: 50.04H: 2.36 Found: C:49.10H: 2.14

EXAMPLE 1bb 8-Bromo-7-hydroxy-3-(4-hydroxyphenyl)-1-naphthonitrile

[0416] The title compound was prepared by reacting8-bromo-7-hydroxy-3-(4-methoxyphenyl)-1-naphthonitrile (0.13 g, 0.37mmol) with boron tribromide (1.1 mL of 1 N solution, 1.1 mmol) accordingto method D to yield 0.050 g (40%) of an off white solid: mp 204-208°C.(d); ¹H NMR (DMSO-d₆): δ 6.90 (2H, d, J=8.30 Hz), 7.41 (1H, d, J=8.79Hz), 7.72 (2H, d, J=8.79 Hz), 8.02 (1H, d, J=9.23 Hz), 8.37 (1H, d,J=1.95 Hz), 8.47 (1H, d, J=2.44 Hz), 9.72 (1H, s), 11.16 (1H, s); MS(ESI) m/z338/340 (M−H).Anal. for C₁₇H₁₀BrNO₂

[0417] Calc'd: C: 60.02H: 2.96 N: 4.12 Found: C: 59.84H: 3.18 N: 3.83.

[0418] Synthesis of Compounds in Scheme 15

Intermediate 91 3-Bromo-8-chloro-7-hydroxy-1-naphthonitrile

[0419] To a mixture of 8-chloro-7-hydroxy-1-naphthonitrile (0.127 g,0.63 mmol) and glacial acetic acid (1 mL) in a pressure tube was added asolution of bromine (0.24 g, 1.5 mmol) in glacial acetic acid (2 mL).The tube was sealed and the mixture was stirred at 100° C. overnight.The reaction was cooled, poured into water (50 mL), and extracted withethyl acetate (3×100 mL). The combined organic layers were washed withsodium bicarbonate solution, dried over sodium sulfate, filtered,stripped of solvent, and purified on a silica column (20% ethylacetate—hexanes) to yield 0.10 g (56%) of the title compound as a yellowsolid. An analytical sample was prepared by preparative reverse phaseHPLC to yield the title compound as a white solid: mp 148-150° C.; ¹HNMR (DMSO-d₆): δ 7.47 (1H, d, J=8.98 Hz), 7.95 (1H, d, J=9.02 Hz), 8.32(1H, d, J=2.08 Hz), 8.55 (1H, d, J=2.08 Hz), 11.33 (1H, s); MS (ESI) m/z280/282/284 (M−H)⁻.

[0420] Anal. for C₁₁H₅BrClNO 0.25H₂O: Calc'd: C: 46.03H: 1.93 N: 4.88Found: C: 45.92H: 1.75 N: 4.78.

Iintermediate 91 3-Bromo-8-chloro-7-hydroxy-1-naphthonitrile

[0421] The title compound was prepared by reacting3-bromo-7-hydroxy-1-naphthonitrile (0.32 g, 1.28 mmol) with NCS (0.24 g,1.8 mmol) in THF (25 mL) at 45° C. for 3 hr according to method C toyield 0.30 g (83%) of a yellow solid. An analytical sample was preparedby preparative reverse phase HPLC to yield the title compound as a whitesolid: mp 148-150° C.; ¹H NMR (DMSO-d₆): δ 7.47 (1H, d, J=8.98 Hz), 7.95(1H, d, J=9.02 Hz), 8.32 (1H, d, J=2.08 Hz), 8.55 (1H, d, J=2.08 Hz),11.33 (1H, s); MS (ESI) m/z280/282/284 (M−H)⁻

[0422] Anal. for C₁₁H₅BrClNO 0.25H₂O: Calc'd: C: 46.03H: 1.93 N: 4.88Found: C: 45.92H: 1.75 N: 4.78.

Intermediate 928-Chloro-3-(3-fluoro-4-methoxyphenyl)-7-hydroxy-1-naphthonitrile

[0423] The title compound was prepared by reacting3-bromo-8-chloro-7-hydroxy-1-naphthonitrile (0.20 g, 0.71 mmol) with3-fluoro-4-methoxyphenylboronic acid (0.17 g, 1.0 mmol) according toMethod A to yield 0.14 (60%) of a yellow solid: mp 198-200° C.;¹H NMR(DMSO-d₆): δ 3.91 (3H, s), 7.27-7.33 (1H, m), 7.45 (1H, d, J=8.93 Hz),7.71-7.74 (1H, m), 7.85 (1H, dd, J=2.23 Hz, J=13.09 Hz), 8.00 (1H, d,J=9.08 Hz), 8.48 (1H, d, J=1.97 Hz), 8.57 (1H, d, J=1.95 Hz), 11.18 (1H,s); MS (ESI) m/z 326/328 (M−H).

[0424] Anal. for C₁₈H₁₁ClFNO2 Calc'd: C: 65.97H: 3.38 N: 4.27 Found: C:65.76H: 3.36 N: 4.11.

EXAMPLE 1aw 8-Chloro-3-(4-hydroxyphenyl)-7-hydroxy-1-naphthonitrile

[0425] The title compound was prepared by reacting3-bromo-8-chloro-7-hydroxy-1-naphthonitrile (0.10 g, 0.37 mmol) with4-tert-butyldimethylsilyloxyphenylboronic acid (0.13 g, 0.52 mmol)according to Method A to yield 0.036 g (33%) of a white solid: mp254-256° C.; ¹H NMR (DMSO-d₆): δ 6.90 (2H, d, J=8.64 Hz), 7.43 (1H, d,J=8.95 Hz), 7.72 (2H, d, J=8.64 Hz), 7.99 (1H, d, J=8.97 Hz), 8.38 (1H,d, J=1.95 Hz), 8.47 (1H, d, J=1.92 Hz), 9.73 (1H, s), 11.08 (1H, s); MS(ESI) m/z 294/296 (M−H)⁻.

[0426] Anal. for C₁₇H₁₀ClNO₂ Calc'd: C: 69.05H: 3.41 N: 4.74 Found: C:69.01H: 3.63 N: 4.31.

EXAMPLE 1ax8-Chloro-3-(3-fluoro-4-hydroxyphenyl)-7-hydroxy-1-naphthonitrile

[0427] The title compound was prepared by reacting8-chloro-3-(3-fluoro-4-methoxyphenyl)-7-hydroxy-1-naphthonitrile (0.042g, 0.13 mmol) with pyridinium HCl (1.8 g) according to method D to yield0.033 g (78%) of a tan solid. This material was further purified bypreparative reverse phase HPLC to yield the title compound as a whitesolid: mp 246-252° C.; ¹H NMR (DMSO-d₆): δ 7.04-7.10 (1H, m), 7.44 91H,d, J=8.94 Hz), 7.56 (1H, dd, J=1.66 Hz, J=8.37 Hz), 7.76 (1H, dd, J=2.20Hz, J=12.88 Hz), 7.99 (1H, d, J=9.09 Hz), 8.43 (1H, d, J=1.98 Hz), 8.52(1H, d, J=1.94 Hz), 10.19 (1H, bs), 11.05 (1H, bs); MS (ESI) m/z312/314(M−H)⁻.

[0428] Anal. for C₁₇H₉ClFNO₂ 0.25H₂O: Calc'd: C: 64.16H: 3.01 N: 4.40Found: C: 63.75H: 2.84 N: 4.20.

What is claimed is:
 1. A compound of formula I, having the structure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R₉ is not hydrogen, or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,having the structure

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim2, wherein the 5 or 6-membered heterocyclic ring having 1 to 4heteroatoms selected from O, N or S is furan, thiophene, or pyridine ora pharmaceutically acceptable salt thereof.
 4. The compound of claim 3,wherein R₅, R₆, R₇, R₈, and R₉ are each, independently, hydrogen,halogen, —CN, or alkynyl of 2-7 carbon atoms or a pharmaceuticallyacceptable salt thereof.
 5. The compound of claim 4, wherein R₆, R₇, andR₈ are hydrogen, or a pharmaceutically acceptable salt thereof.
 6. Acompound of claim 1, which is8-fluoro-6-(3-fluoro-4-hydroxyphenyl)-2-naphthol or a pharmaceuticallyacceptable salt thereof.
 7. A compound of claim 1, which is1-chloro-8-fluoro-6-(3-fluoro-4-hydroxyphenyl)-2-naphthol or apharmaceutically acceptable salt thereof.
 8. A compound of claim 1,which is 3-(3-fluoro-4-hydroxyphenyl)-7-hydroxy-1-naphthonitrile or apharmaceutically acceptable salt thereof.
 9. A compound of claim 1,which is 3-(3,5-difluoro-4-hydroxyphenyl)-7-hydroxy-1-naphthonitrile ora pharmaceutically acceptable salt thereof.
 10. A compound which is a)7-(4-hydroxyphenyl)-2-naphthol; b) 7-(3-hydroxyphenyl)-2-naphthol; c)6-(4-hydroxyphenyl)-1-naphthol; d) 6-phenyl-2-naphthol; e)6-(3-hydroxyphenyl)-2-naphthol; f) 6-(3-chlorophenyl)-2-naphthol; g)2-fluoro-4-(2-naphthyl)phenol; h)6-(3-fluoro-4-hydroxyphenyl)-2-naphthol; i)6-(3-chloro-4-hydroxyphenol)-2-naphthol; j)1-chloro-6-phenyl-2-naphthol; k) 1-bromo-6-(4-hydroxyphenyl)-2-naphthol;l) 1-chloro-6-(4-hydroxyphenyl)-2-naphthol; m)1-fluoro-6-(4-hydroxyphenyl)-2-naphthol; n)2-hydroxy-6-(4-hydroxyphenyl)-1-naphthonitrile; o)6-(4-hydroxyphenyl)-1-phenyl-2-naphthol; p)6-(4-hydroxyphenyl)-1-methyl-2-naphthol; q)1-chloro-6-(3-fluoro-4-hydroxyphenyl)-2-naphthol; r)1-chloro-6-(3-chloro-4-hydroxyphenyl)-2-naphthol; s)6-(4-hydroxyphenyl)-1-nitro-2-naphthol; t)1-chloro-6-(4-hydroxy-2-methylphenyl)-2-naphthol; u)6-(4-hydroxy-2-methylphenyl)-2-naphthol; v)6-(4-hydroxy-2-methoxyphenyl)-2-naphthol; w)6-(2-chloro-4-hydroxyphenyl)-2-naphthol; x)1-chloro-6-(2-chloro-4-hydroxyphenyl)-2-naphthol; y)6-(2-fluoro-4-hydroxyphenyl)-2-naphthol; z)6-(2,5-difluoro-4-hydroxyphenyl)-2-naphthol; aa)6-(2,6-difluoro-4-hydroxyphenyl)-2-naphthol; bb)1-chloro-6-(2-fluoro-4-hydroxyphenyl)-2-naphthol; cc)1-chloro-6-(2,5-difluoro-4-hydroxyphenyl)-2-naphthol; dd)1-chloro-6-(2,6-difluoro-4-hydroxyphenyl)-2-naphthol; ee)8-fluoro-6-(4-hydroxyphenyl)-2-naphthol; ff)1-chloro-8-fluoro-6-(4-hydroxyphenyl)-2-naphthol; gg)8-chloro-6-(4-hydroxyphenyl)-2-naphthol; hh)1,5-dichloro-8-fluoro-6-(4-hydroxyphenyl)-2-naphthol; ii)2-chloro-4-(2-naphthyl)phenol; jj)3-bromo-8-chloro-6-(4-hydroxyphenyl)-2-naphthol; kk)1,8-dichloro-6-(4-hydroxyphenyl)-2-naphthol; ll)3-bromo-1,8-dichloro-6-(4-hydroxyphenyl)-2-naphthol; mm)7-hydroxy-3-(4-hydroxyphenyl)-1-naphthonitrile; nn)8-chloro-3-(4-hydroxyphenyl)-7-hydroxy-1-naphthonitrile; oo)8-chloro-3-(3-fluoro-4-hydroxyphenyl)-7-hydroxy-1-naphthonitrile; pp)6-(3,5-difluoro-4-hydroxyphenyl)-2-naphthol; qq)1-chloro-6-(3,5-difluoro-4-hydroxyphenyl)-2-naphthol; rr)8-bromo-7-hydroxy-3-(4-hydroxyphenyl)-1-naphthonitrile or apharmaceutically acceptable salt thereof.
 11. A method of treating orinhibiting prostatitis or interstitial cystitis in a mammal in needthereof, which comprises providing to said mammal an effective amount ofa compound of formula I, having the structure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R₉ is not hydrogen, or apharmaceutically acceptable salt thereof.
 12. A method of treating orinhibiting inflammatory bowel disease, Crohn's disease, ulcerativeproctitis, or colitis in a mammal in need thereof, which comprisesproviding to said mammal an effective amount of a compound of formula I,having the structure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R₉ is not hydrogen, or apharmaceutically acceptable salt thereof.
 13. A method of treating orinhibiting prostatic hypertrophy, uterine leiomyomas, breast cancer,endometrial cancer, polycystic ovary syndrome, endometrial polyps,benign breast disease, adenomyosis, ovarian cancer, melanoma, prostratecancer, colon cancer, glioma or astioblastomia in a mammal in needthereof, which comprises providing to said mammal an effective amount ofa compound of formula I, having the structure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R₉ is not hydrogen, or apharmaceutically acceptable salt thereof.
 14. A method of loweringcholesterol, triglycerides, Lp(a), or LDL levels; inhibiting or treatinghypercholesteremia; hyperlipidemia; cardiovascular disease;atherosclerosis; hypertension; peripheral vascular disease; restenosis,or vasospasm; or inhibiting vascular wall damage from cellular eventsleading toward immune mediated vascular damage in a mammal in needthereof, which comprises providing to said mammal an effective amount ofa compound of formula I, having the structure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R₉ is not hydrogen, or apharmaceutically acceptable salt thereof.
 15. A method of providingcognition enhancement or neuroprotection; or treating or inhibitingsenile dementias, Alzheimer's disease, cognitive decline, stroke,anxiety, or neurodegenerative disorders in a mammal in need thereof,which comprises providing to said mammal an effective amount of acompound of formula I, having the structure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R⁹ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R⁹ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R⁹, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R₉ is not hydrogen, or apharmaceutically acceptable salt thereof.
 16. A method of treating orinhibiting free radical induced disease states in a mammal in needthereof, which comprises providing to said mammal an effective amount ofa compound of formula I, having the structure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R⁹ is not hydrogen, or apharmaceutically acceptable salt thereof.
 17. A method of treating orinhibiting vaginal or vulvar atrophy; atrophic vaginitis; vaginaldryness; pruritus; dyspareunia; dysuria; frequent urination; urinaryincontinence; urinary tract infections in a mammal in need thereof,which comprises providing to said mammal an effective amount of acompound of formula I, having the structure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R₉ is not hydrogen, or apharmaceutically acceptable salt thereof.
 18. A method of treating orinhibiting vasomotor symptoms in a mammal in need thereof, whichcomprises providing to said mammal an effective amount of a compound offormula I, having the structure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R₉ is not hydrogen, or apharmaceutically acceptable salt thereof.
 19. A method of inhibitingconception in a mammal in need thereof, which comprises providing tosaid mammal an effective amount of a compound of formula I, having thestructure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R⁹ is not hydrogen, or apharmaceutically acceptable salt thereof.
 20. A method of treating orinhibiting arthritis in a mammal in need thereof, which comprisesproviding to said mammal an effective amount of a compound of formula I,having the structure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R₉ is not hydrogen, or apharmaceutically acceptable salt thereof.
 21. The method according toclaim 20, wherein the arthritis is rheumatoid arthritis, osteoarthritis,or spondyloarthropathies.
 22. A method of treating or inhibiting jointswelling or erosion; or treating or inhibiting joint damage secondary toarthroscopic or surgical procedures in a mammal in need thereof, whichcomprises providing to said mammal an effective amount of a compound offormula I, having the structure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R₉ is not hydrogen, or apharmaceutically acceptable salt thereof.
 23. A method of treating orinhibiting psoriasis or dermatitis in a mammal in need thereof, whichcomprises providing to said mammal an effective amount of a compound offormula I, having the structure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R₉ is not hydrogen, or apharmaceutically acceptable salt thereof.
 24. A method of treating orinhibiting ischemia, reperfusion injury, asthma, pleurisy, multiplesclerosis, systemic lupus erythematosis, uveitis, sepsis, hemmorhagicshock, macular degeneration or type II diabetes in a mammal in needthereof, which comprises providing to said mammal an effective amount ofa compound of formula I, having the structure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R₉ is not hydrogen, or apharmaceutically acceptable salt thereof.
 25. A method of treating orinhibiting endometriosis in a mammal in need thereof, which comprisesproviding to said mammal an effective amount of a compound of formula I,having the structure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R₉ is not hydrogen, or apharmaceutically acceptable salt thereof.
 26. A pharmaceuticalcomposition which comprises a compound of formula I, having thestructure

wherein R₁ and R₂ are each, independently, selected from hydrogen,hydroxyl, alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, andalkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen; R₅,R₆, R₇, R₈, and R₉ are each, independently, hydrogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,halogen, alkoxy of 1-6 carbon atoms, —CN, —CHO, trifluoromethyl,phenylalkyl of 7-12 carbon atoms, phenyl, or a 5 or 6-memberedheterocyclic ring having 1 to 4 heteroatoms selected from O, N or S;wherein the alkyl or alkenyl moieties of R₅, R₆, R₇, R₈, or R₉ may beoptionally substituted with hydroxyl, —CN, halogen, trifluroalkyl,trifluoroalkoxy, —NO₂, or phenyl; wherein the phenyl moiety of R₅, R₆,R₇, R₈, R₉, or R₁₀ may be optionally mono-, di-, or tri-subsititutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, halogen, —CN, —NO₂, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; with theproviso that at least one of R₅ or R₉ is not hydrogen, or apharmaceutically acceptable salt thereof, and a pharmaceutical carrier.